@bgicli/bgicli 2.1.1 → 2.2.1

package/data/skills/tooluniverse-structural-variant-analysis/SKILL.md

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+---
+name: tooluniverse-structural-variant-analysis
+description: Comprehensive structural variant (SV) analysis skill for clinical genomics. Classifies SVs (deletions, duplications, inversions, translocations), assesses pathogenicity using ACMG-adapted criteria, evaluates gene disruption and dosage sensitivity, and provides clinical interpretation with evidence grading. Use when analyzing CNVs, large deletions/duplications, chromosomal rearrangements, or any structural variants requiring clinical interpretation.
+---
+
+# Structural Variant Analysis Workflow
+
+Systematic analysis of structural variants (deletions, duplications, inversions, translocations, complex rearrangements) for clinical genomics interpretation using ACMG-adapted criteria.
+
+**KEY PRINCIPLES**:
+1. **Report-first approach** - Create SV_analysis_report.md FIRST, then populate progressively
+2. **ACMG-style classification** - Pathogenic/Likely Pathogenic/VUS/Likely Benign/Benign with explicit evidence
+3. **Evidence grading** - Grade all findings by confidence level (★★★/★★☆/★☆☆)
+4. **Dosage sensitivity critical** - Gene dosage effects drive SV pathogenicity
+5. **Breakpoint precision matters** - Exact gene disruption vs dosage-only effects
+6. **Population context essential** - gnomAD SVs for frequency assessment
+7. **English-first queries** - Always use English terms in tool calls (gene names, disease names), even if the user writes in another language. Only try original-language terms as a fallback. Respond in the user's language
+
+---
+
+## Problem This Skill Solves
+
+Structural variants (SVs) present unique interpretation challenges:
+
+1. **Complex molecular consequences** - SVs can cause gene dosage changes, gene disruption, gene fusions, position effects
+2. **Size matters** - Pathogenicity depends on size, gene content, and breakpoint precision
+3. **Limited databases** - Fewer curated SVs in ClinVar compared to SNVs
+4. **Dosage sensitivity** - Haploinsufficiency and triplosensitivity are critical but gene-specific
+5. **Population frequency** - Large benign CNVs are common; distinguishing pathogenic from benign is challenging
+
+**This skill provides**: A systematic workflow integrating SV classification, gene content analysis, dosage sensitivity assessment, population frequencies, and ACMG-adapted criteria into clinically actionable interpretations.
+
+---
+
+## Triggers
+
+Use this skill when users:
+- Ask about structural variant interpretation
+- Have CNV data from array or sequencing
+- Ask "is this deletion/duplication pathogenic?"
+- Need ACMG classification for SVs
+- Want to assess gene dosage effects
+- Ask about chromosomal rearrangements
+- Have large-scale genomic alterations requiring interpretation
+
+---
+
+## Workflow Overview
+
+```
+┌─────────────────────────────────────────────────────────────────┐
+│              STRUCTURAL VARIANT INTERPRETATION                   │
+├─────────────────────────────────────────────────────────────────┤
+│                                                                  │
+│  Phase 1: SV IDENTITY & CLASSIFICATION                          │
+│  ├── Normalize SV coordinates (hg19/hg38)                       │
+│  ├── Determine SV type (DEL/DUP/INV/TRA/CPX)                   │
+│  ├── Calculate SV size                                          │
+│  └── Assess breakpoint precision                                │
+│                                                                  │
+│  Phase 2: GENE CONTENT ANALYSIS                                  │
+│  ├── Identify genes fully contained in SV                       │
+│  ├── Identify genes with breakpoints (disrupted)                │
+│  ├── Annotate gene function and disease associations            │
+│  ├── Identify regulatory elements affected                      │
+│  └── Assess gene orientation (for inversions/translocations)    │
+│                                                                  │
+│  Phase 3: DOSAGE SENSITIVITY ASSESSMENT                          │
+│  ├── ClinGen dosage sensitivity scores                          │
+│  │   └─ Haploinsufficiency / Triplosensitivity ratings          │
+│  ├── DECIPHER haploinsufficiency predictions                    │
+│  ├── pLI scores (gnomAD) for loss-of-function intolerance       │
+│  ├── OMIM gene-disease associations (dominant/recessive)        │
+│  └── Known dosage-sensitive genes from literature               │
+│                                                                  │
+│  Phase 4: POPULATION FREQUENCY CONTEXT                           │
+│  ├── gnomAD SV database (overlapping SVs)                       │
+│  ├── DGV (Database of Genomic Variants)                         │
+│  ├── ClinVar (known pathogenic/benign SVs)                      │
+│  └── Calculate reciprocal overlap with population SVs           │
+│                                                                  │
+│  Phase 5: PATHOGENICITY SCORING                                  │
+│  ├── Pathogenicity score (0-10 scale)                           │
+│  │   ├─ Gene content weight (40%)                               │
+│  │   ├─ Dosage sensitivity weight (30%)                         │
+│  │   ├─ Population frequency weight (20%)                       │
+│  │   └─ Inheritance/phenotype match weight (10%)                │
+│  ├── Apply ACMG SV criteria                                     │
+│  └── Generate classification recommendation                      │
+│                                                                  │
+│  Phase 6: LITERATURE & CLINICAL EVIDENCE                         │
+│  ├── PubMed: Similar SVs, gene disruption studies               │
+│  ├── DECIPHER: Developmental disorder cases                     │
+│  ├── Clinical case reports                                      │
+│  └── Functional evidence for gene dosage effects                │
+│                                                                  │
+│  Phase 7: ACMG-ADAPTED CLASSIFICATION                            │
+│  ├── Apply SV-specific evidence codes                           │
+│  ├── Calculate final classification                             │
+│  ├── Identify limiting factors                                  │
+│  └── Generate clinical recommendations                          │
+│                                                                  │
+└─────────────────────────────────────────────────────────────────┘
+```
+
+---
+
+## Phase Details
+
+### Phase 1: SV Identity & Classification
+
+**Goal**: Standardize SV notation and classify type
+
+**SV Types**:
+| Type | Abbreviation | Description | Molecular Effect |
+|------|--------------|-------------|------------------|
+| **Deletion** | DEL | Loss of genomic segment | Haploinsufficiency, gene disruption |
+| **Duplication** | DUP | Gain of genomic segment | Triplosensitivity, gene dosage imbalance |
+| **Inversion** | INV | Segment flipped in orientation | Gene disruption at breakpoints, position effects |
+| **Translocation** | TRA | Segment moved to different chromosome | Gene fusions, disruption, position effects |
+| **Complex** | CPX | Multiple rearrangement types | Variable effects |
+
+**Key Information to Capture**:
+- Chromosome(s) involved
+- Coordinates (start, end) in hg19/hg38
+- SV size (bp or Mb)
+- SV type (DEL/DUP/INV/TRA/CPX)
+- Breakpoint precision (±50bp, ±1kb, etc.)
+- Inheritance pattern (de novo, inherited, unknown)
+
+**Example**:
+```
+SV: arr[GRCh38] 17q21.31(44039927-44352659)x1
+- Type: Deletion (heterozygous)
+- Size: 313 kb
+- Genes: MAPT, KANSL1 (fully contained)
+- Breakpoints: Well-defined (array resolution ±5kb)
+```
+
+---
+
+### Phase 2: Gene Content Analysis
+
+**Goal**: Comprehensive annotation of genes affected by SV
+
+**Tools**:
+| Tool | Purpose | Key Data |
+|------|---------|----------|
+| `Ensembl_lookup_gene` | Gene structure, coordinates | Gene boundaries, exons, transcripts |
+| `NCBI_gene_search` | Gene information | Official symbol, aliases, description |
+| `Gene_Ontology_get_term_info` | Gene function | Biological process, molecular function |
+| `OMIM_search`, `OMIM_get_entry` | Disease associations | Inheritance, clinical features |
+| `DisGeNET_search_gene` | Gene-disease associations | Evidence scores |
+
+**Gene Categories**:
+
+1. **Fully contained genes** - Entire gene within SV boundaries
+   - Deletion: Complete loss of one copy (haploinsufficiency)
+   - Duplication: Extra copy (triplosensitivity)
+
+2. **Partially disrupted genes** - Breakpoint within gene
+   - Likely loss-of-function for affected allele
+   - Check if critical domains disrupted
+
+3. **Flanking genes** - Within 1 Mb of breakpoints
+   - May be affected by position effects
+   - Regulatory disruption possible
+
+**Example Gene Content Analysis**:
+
+```python
+def analyze_gene_content(tu, chrom, sv_start, sv_end, sv_type):
+    """
+    Identify and annotate all genes within SV region.
+    """
+    genes = {
+        'fully_contained': [],
+        'partially_disrupted': [],
+        'flanking': []
+    }
+
+    # Use Ensembl to find overlapping genes
+    # This is pseudocode - actual implementation depends on available tools
+
+    for gene in genes_in_region:
+        gene_start = gene['start']
+        gene_end = gene['end']
+
+        # Classify gene relationship to SV
+        if gene_start >= sv_start and gene_end <= sv_end:
+            # Fully contained
+            gene_info = annotate_gene(tu, gene['symbol'])
+            genes['fully_contained'].append(gene_info)
+
+        elif (gene_start < sv_start < gene_end) or (gene_start < sv_end < gene_end):
+            # Partially disrupted
+            gene_info = annotate_gene(tu, gene['symbol'])
+            genes['partially_disrupted'].append(gene_info)
+
+        elif abs(gene_start - sv_end) < 1000000 or abs(gene_end - sv_start) < 1000000:
+            # Flanking (within 1 Mb)
+            gene_info = annotate_gene(tu, gene['symbol'])
+            genes['flanking'].append(gene_info)
+
+    return genes
+
+def annotate_gene(tu, gene_symbol):
+    """
+    Comprehensive gene annotation.
+    """
+    # OMIM associations
+    omim = tu.tools.OMIM_search(
+        operation="search",
+        query=gene_symbol,
+        limit=5
+    )
+
+    # DisGeNET associations
+    disgenet = tu.tools.DisGeNET_search_gene(
+        operation="search_gene",
+        gene=gene_symbol,
+        limit=10
+    )
+
+    # Gene Ontology
+    # Note: Need gene ID first
+    ncbi = tu.tools.NCBI_gene_search(
+        term=gene_symbol,
+        organism="human"
+    )
+
+    return {
+        'symbol': gene_symbol,
+        'omim': omim,
+        'disgenet': disgenet,
+        'ncbi': ncbi
+    }
+```
+
+**Report Section**:
+```markdown
+### 2.1 Fully Contained Genes (Complete Dosage Effect)
+
+| Gene | Function | Disease Association | Inheritance | Evidence |
+|------|----------|---------------------|-------------|----------|
+| **MAPT** | Microtubule-associated protein tau | Frontotemporal dementia (AD) | Autosomal Dominant | ★★★ |
+| **KANSL1** | Histone acetyltransferase complex | Koolen-De Vries syndrome (AD) | Autosomal Dominant | ★★★ |
+
+**Interpretation**: Deletion results in haploinsufficiency of two dosage-sensitive genes. KANSL1 haploinsufficiency is the primary cause of pathogenicity.
+
+*Sources: OMIM, DisGeNET, Ensembl*
+
+### 2.2 Partially Disrupted Genes (Breakpoint Within Gene)
+
+| Gene | Breakpoint Location | Effect | Critical Domains Lost |
+|------|-------------------|--------|----------------------|
+| **NF1** | Intron 28 of 58 | 5' portion deleted | Yes - GTPase-activating domain |
+
+**Interpretation**: Breakpoint disrupts NF1 coding sequence, likely resulting in loss-of-function. NF1 is haploinsufficient (causes neurofibromatosis type 1).
+
+### 2.3 Flanking Genes (Potential Position Effects)
+
+| Gene | Distance from SV | Regulatory Risk | Evidence |
+|------|------------------|-----------------|----------|
+| **KCNJ2** | 450 kb upstream | Low | ★☆☆ |
+
+**Note**: Position effects are possible but less common. Consider if phenotype unexplained by contained genes.
+```
+
+---
+
+### Phase 3: Dosage Sensitivity Assessment
+
+**Goal**: Determine if affected genes are dosage-sensitive
+
+**Tools**:
+| Tool | Purpose | Key Data |
+|------|---------|----------|
+| `ClinGen_search_dosage_sensitivity` | Gold standard curation | HI/TS scores (0-3) |
+| `ClinGen_search_gene_validity` | Gene-disease validity | Definitive/Strong/Moderate |
+| `gnomad_search` (pLI) | Loss-of-function intolerance | pLI score (0-1) |
+| `DECIPHER_search` | Developmental disorders | Patient phenotypes with similar SVs |
+| `OMIM_get_entry` | Inheritance pattern | AD/AR indicates dosage sensitivity |
+
+**ClinGen Dosage Sensitivity Scores**:
+
+| Score | Haploinsufficiency (HI) | Triplosensitivity (TS) | Interpretation |
+|-------|------------------------|------------------------|----------------|
+| **3** | Sufficient evidence | Sufficient evidence | Gene IS dosage-sensitive |
+| **2** | Emerging evidence | Emerging evidence | Likely dosage-sensitive |
+| **1** | Little evidence | Little evidence | Insufficient evidence |
+| **0** | No evidence | No evidence | No established dosage sensitivity |
+
+**pLI Score Interpretation** (gnomAD):
+| pLI Range | Interpretation | LoF Intolerance |
+|-----------|----------------|-----------------|
+| **≥0.9** | Extremely intolerant | High - likely haploinsufficient |
+| **0.5-0.9** | Moderately intolerant | Moderate |
+| **<0.5** | Tolerant | Low - likely NOT haploinsufficient |
+
+**Implementation**:
+
+```python
+def assess_dosage_sensitivity(tu, gene_list):
+    """
+    Assess dosage sensitivity for all genes in SV.
+    Returns dosage scores and interpretation.
+    """
+    dosage_data = []
+
+    for gene_symbol in gene_list:
+        # 1. ClinGen dosage sensitivity (gold standard)
+        clingen = tu.tools.ClinGen_search_dosage_sensitivity(
+            gene=gene_symbol
+        )
+
+        hi_score = None
+        ts_score = None
+        if clingen.get('data'):
+            for entry in clingen['data']:
+                hi_score = entry.get('Haploinsufficiency Score')
+                ts_score = entry.get('Triplosensitivity Score')
+                break
+
+        # 2. ClinGen gene validity (supports dosage sensitivity)
+        validity = tu.tools.ClinGen_search_gene_validity(
+            gene=gene_symbol
+        )
+
+        validity_level = None
+        if validity.get('data'):
+            for entry in validity['data']:
+                validity_level = entry.get('Classification')
+                break
+
+        # 3. pLI score from gnomAD (if available via gene search)
+        # Note: May need to use myvariant or other tools
+        # pli_score = get_pli_score(tu, gene_symbol)
+
+        # 4. OMIM inheritance pattern
+        omim = tu.tools.OMIM_search(
+            operation="search",
+            query=gene_symbol,
+            limit=3
+        )
+
+        inheritance_pattern = None
+        if omim.get('data', {}).get('entries'):
+            for entry in omim['data']['entries']:
+                mim = entry.get('mimNumber')
+                details = tu.tools.OMIM_get_entry(
+                    operation="get_entry",
+                    mim_number=str(mim)
+                )
+                # Extract inheritance from details
+                # inheritance_pattern = parse_inheritance(details)
+
+        # Integrate evidence
+        dosage_assessment = {
+            'gene': gene_symbol,
+            'hi_score': hi_score,
+            'ts_score': ts_score,
+            'validity_level': validity_level,
+            'inheritance': inheritance_pattern,
+            'is_dosage_sensitive': (hi_score == '3' or ts_score == '3'),
+            'evidence_grade': calculate_evidence_grade(hi_score, ts_score, validity_level)
+        }
+
+        dosage_data.append(dosage_assessment)
+
+    return dosage_data
+
+def calculate_evidence_grade(hi_score, ts_score, validity):
+    """
+    Calculate evidence grade for dosage sensitivity.
+    """
+    if (hi_score == '3' or ts_score == '3') and validity == 'Definitive':
+        return '★★★'  # High confidence
+    elif (hi_score in ['2', '3'] or ts_score in ['2', '3']):
+        return '★★☆'  # Moderate confidence
+    else:
+        return '★☆☆'  # Low confidence
+```
+
+**Report Section**:
+```markdown
+### 3. Dosage Sensitivity Assessment
+
+#### Haploinsufficient Genes (Deletions/Disruptions)
+
+| Gene | ClinGen HI Score | pLI | Validity | Disease | Evidence |
+|------|-----------------|-----|----------|---------|----------|
+| **KANSL1** | 3 (Sufficient) | 0.99 | Definitive | Koolen-De Vries syndrome | ★★★ |
+| **MAPT** | 2 (Emerging) | 0.85 | Strong | FTD (rare) | ★★☆ |
+
+**Interpretation**: KANSL1 has definitive evidence for haploinsufficiency. Deletion of one copy is expected to cause Koolen-De Vries syndrome (intellectual disability, hypotonia, distinctive facial features).
+
+*Sources: ClinGen Dosage Sensitivity Map, gnomAD pLI*
+
+#### Triplosensitive Genes (Duplications)
+
+| Gene | ClinGen TS Score | Disease Mechanism | Evidence |
+|------|-----------------|-------------------|----------|
+| **MECP2** | 3 (Sufficient) | MECP2 duplication syndrome | ★★★ |
+| **PMP22** | 3 (Sufficient) | Charcot-Marie-Tooth 1A | ★★★ |
+
+**Note**: For this deletion, triplosensitivity is not applicable. Listed for reference.
+
+#### Non-Dosage-Sensitive Genes
+
+| Gene | HI Score | TS Score | Interpretation |
+|------|----------|----------|----------------|
+| **GENE_X** | 0 | 0 | No established dosage sensitivity |
+| **GENE_Y** | 1 | 1 | Insufficient evidence |
+
+**Interpretation**: These genes lack evidence for dosage sensitivity. Deletion/duplication less likely to be pathogenic solely due to these genes.
+```
+
+---
+
+### Phase 4: Population Frequency Context
+
+**Goal**: Determine if SV is common in general population (likely benign) or rare (supports pathogenicity)
+
+**Tools**:
+| Tool | Purpose | Key Data |
+|------|---------|----------|
+| `gnomad_search` | Population SV frequencies | Overlapping SVs, frequencies |
+| `ClinVar_search_variants` | Known pathogenic/benign SVs | Classification, review status |
+| `DECIPHER_search` | Patient SVs with phenotypes | Case reports, phenotype similarity |
+
+**Frequency Interpretation** (adapted from ACMG):
+
+| SV Frequency | ACMG Code | Interpretation |
+|--------------|-----------|----------------|
+| **≥1% in gnomAD SVs** | BA1 (Stand-alone Benign) | Too common for rare disease |
+| **0.1-1%** | BS1 (Strong Benign) | Likely benign common variant |
+| **<0.01%** | PM2 (Supporting Pathogenic) | Rare, supports pathogenicity |
+| **Absent** | PM2 (Supporting) | Very rare, supports pathogenicity |
+
+**Reciprocal Overlap Calculation**:
+
+For proper comparison, calculate reciprocal overlap between query SV and population SV:
+
+```
+Reciprocal Overlap = min(overlap_with_A, overlap_with_B)
+where:
+  overlap_with_A = (overlap length) / (SV_A length)
+  overlap_with_B = (overlap length) / (SV_B length)
+
+Threshold: ≥70% reciprocal overlap = "same" SV
+```
+
+**Implementation**:
+
+```python
+def assess_population_frequency(tu, chrom, sv_start, sv_end, sv_type):
+    """
+    Check population databases for overlapping SVs.
+    """
+    # 1. Check ClinVar for known pathogenic/benign SVs
+    clinvar = tu.tools.ClinVar_search_variants(
+        chromosome=str(chrom),
+        start=sv_start,
+        stop=sv_end,
+        variant_type=sv_type.upper()
+    )
+
+    known_svs = []
+    if clinvar.get('data'):
+        for variant in clinvar['data']:
+            classification = variant.get('clinical_significance')
+            known_svs.append({
+                'database': 'ClinVar',
+                'classification': classification,
+                'review_status': variant.get('review_status'),
+                'coordinates': f"{variant.get('chromosome')}:{variant.get('start')}-{variant.get('stop')}"
+            })
+
+    # 2. gnomAD SVs (if available)
+    # Note: gnomAD SV database may not have direct API access via ToolUniverse
+    # May need to use genomic coordinate search
+
+    # 3. DECIPHER for similar patient cases
+    decipher_search = tu.tools.DECIPHER_search(
+        query=f"chr{chrom}:{sv_start}-{sv_end}",
+        search_type="region"
+    )
+
+    patient_cases = []
+    if decipher_search.get('data'):
+        patient_cases = decipher_search['data']
+
+    return {
+        'clinvar_matches': known_svs,
+        'decipher_cases': patient_cases,
+        'frequency_interpretation': interpret_frequency(known_svs)
+    }
+
+def interpret_frequency(known_svs):
+    """
+    Interpret frequency based on ClinVar matches.
+    """
+    if any(sv['classification'] == 'Benign' for sv in known_svs):
+        return {
+            'acmg_code': 'BA1 or BS1',
+            'interpretation': 'Likely benign based on ClinVar benign classification',
+            'evidence_grade': '★★★'
+        }
+    elif any(sv['classification'] == 'Pathogenic' for sv in known_svs):
+        return {
+            'acmg_code': 'PS1',
+            'interpretation': 'Pathogenic based on ClinVar pathogenic classification',
+            'evidence_grade': '★★★'
+        }
+    else:
+        return {
+            'acmg_code': 'PM2',
+            'interpretation': 'Rare variant, not found in ClinVar or population databases',
+            'evidence_grade': '★★☆'
+        }
+```
+
+**Report Section**:
+```markdown
+### 4. Population Frequency Context
+
+#### ClinVar Matches (Overlapping SVs)
+
+| VCV ID | Classification | Size | Overlap | Review Status | Genes |
+|--------|----------------|------|---------|---------------|-------|
+| VCV000012345 | Pathogenic | 320 kb | 95% reciprocal | ★★★ Reviewed by expert panel | KANSL1, MAPT |
+
+**Match Found**: Query deletion has 95% reciprocal overlap with known pathogenic deletion in ClinVar (VCV000012345). This is the Koolen-De Vries syndrome deletion.
+
+**ACMG Code**: **PS1** (Strong) - Same genomic region as established pathogenic SV
+
+*Source: ClinVar via `ClinVar_search_variants`*
+
+#### gnomAD SV Database
+
+**Search Result**: No overlapping deletions found in gnomAD SV v4.0 (>10,000 genomes)
+
+**Interpretation**: Absence from gnomAD supports rarity and pathogenic potential.
+
+**ACMG Code**: **PM2** (Moderate) - Absent from population databases
+
+*Note: gnomAD SVs queried via browser (no direct API access)*
+
+#### DECIPHER Patient Cases
+
+| Case ID | Phenotype | SV Type | Size | Overlap | Similarity |
+|---------|-----------|---------|------|---------|------------|
+| 12345 | Intellectual disability, hypotonia | DEL | 315 kb | 98% | High |
+| 67890 | Developmental delay, facial dysmorphism | DEL | 305 kb | 92% | High |
+
+**Phenotype Match**: 8/10 DECIPHER patients have intellectual disability and hypotonia, consistent with Koolen-De Vries syndrome.
+
+**ACMG Support**: **PP4** (Supporting) - Patient phenotype consistent with gene's disease association
+
+*Source: DECIPHER via `DECIPHER_search`*
+```
+
+---
+
+### Phase 5: Pathogenicity Scoring
+
+**Goal**: Quantitative pathogenicity assessment (0-10 scale)
+
+**Scoring Components**:
+
+1. **Gene Content (40 points max)**:
+   - 10 points per dosage-sensitive gene (HI/TS score 3)
+   - 5 points per likely dosage-sensitive gene (score 2)
+   - 2 points per gene with disease association
+   - Cap at 40 points
+
+2. **Dosage Sensitivity Evidence (30 points max)**:
+   - 30 points: Multiple genes with definitive HI/TS (score 3)
+   - 20 points: One gene with definitive HI/TS
+   - 10 points: Genes with emerging evidence (score 2)
+   - 5 points: Predicted haploinsufficiency (pLI >0.9)
+
+3. **Population Frequency (20 points max)**:
+   - 20 points: Absent from gnomAD, DGV
+   - 10 points: Rare (<0.01%)
+   - 0 points: Common (>0.1%)
+   - -20 points: Very common (>1%) - likely benign
+
+4. **Clinical Evidence (10 points max)**:
+   - 10 points: Matching ClinVar pathogenic SV
+   - 8 points: DECIPHER cases with matching phenotype
+   - 5 points: Literature support for gene dosage effects
+   - 3 points: Phenotype consistent with genes
+
+**Pathogenicity Score Interpretation**:
+
+| Score | Classification | Confidence | Interpretation |
+|-------|----------------|------------|----------------|
+| **9-10** | Pathogenic | ★★★ | High confidence pathogenic |
+| **7-8** | Likely Pathogenic | ★★☆ | Strong evidence for pathogenicity |
+| **4-6** | VUS | ★☆☆ | Uncertain significance |
+| **2-3** | Likely Benign | ★★☆ | Strong evidence for benign |
+| **0-1** | Benign | ★★★ | High confidence benign |
+
+**Implementation**:
+
+```python
+def calculate_pathogenicity_score(gene_content, dosage_data, frequency_data, clinical_data):
+    """
+    Calculate comprehensive pathogenicity score (0-10 scale).
+    """
+    score = 0
+    breakdown = {}
+
+    # 1. Gene content scoring (40 points max)
+    gene_score = 0
+    for gene in gene_content['fully_contained'] + gene_content['partially_disrupted']:
+        dosage_info = next((d for d in dosage_data if d['gene'] == gene['symbol']), None)
+        if dosage_info:
+            if dosage_info['hi_score'] == '3':
+                gene_score += 10
+            elif dosage_info['hi_score'] == '2':
+                gene_score += 5
+            elif gene.get('omim_disease'):
+                gene_score += 2
+
+    gene_score = min(gene_score, 40)  # Cap at 40
+    breakdown['gene_content'] = gene_score / 40 * 4  # Scale to 0-4
+
+    # 2. Dosage sensitivity scoring (30 points max)
+    dosage_score = 0
+    definitive_genes = sum(1 for d in dosage_data if d['hi_score'] == '3')
+
+    if definitive_genes >= 2:
+        dosage_score = 30
+    elif definitive_genes == 1:
+        dosage_score = 20
+    else:
+        emerging_genes = sum(1 for d in dosage_data if d['hi_score'] == '2')
+        dosage_score = emerging_genes * 5
+
+    dosage_score = min(dosage_score, 30)
+    breakdown['dosage_sensitivity'] = dosage_score / 30 * 3  # Scale to 0-3
+
+    # 3. Population frequency scoring (20 points max)
+    freq_score = 0
+    if frequency_data.get('frequency') is None:
+        freq_score = 20  # Absent
+    elif frequency_data['frequency'] < 0.0001:
+        freq_score = 10  # Rare
+    elif frequency_data['frequency'] < 0.001:
+        freq_score = 5  # Uncommon
+    elif frequency_data['frequency'] > 0.01:
+        freq_score = -20  # Common - likely benign
+
+    breakdown['population_frequency'] = freq_score / 20 * 2  # Scale to -2 to 2
+
+    # 4. Clinical evidence scoring (10 points max)
+    clinical_score = 0
+    if clinical_data.get('clinvar_pathogenic'):
+        clinical_score = 10
+    elif clinical_data.get('decipher_matching_phenotype'):
+        clinical_score = 8
+    elif clinical_data.get('literature_support'):
+        clinical_score = 5
+
+    clinical_score = min(clinical_score, 10)
+    breakdown['clinical_evidence'] = clinical_score / 10 * 1  # Scale to 0-1
+
+    # Total score (0-10 scale)
+    total_score = breakdown['gene_content'] + breakdown['dosage_sensitivity'] + \
+                  breakdown['population_frequency'] + breakdown['clinical_evidence']
+
+    total_score = max(0, min(10, total_score))  # Ensure 0-10 range
+
+    return {
+        'total_score': round(total_score, 1),
+        'breakdown': breakdown,
+        'classification': classify_score(total_score)
+    }
+
+def classify_score(score):
+    """Map score to ACMG-style classification."""
+    if score >= 9:
+        return 'Pathogenic'
+    elif score >= 7:
+        return 'Likely Pathogenic'
+    elif score >= 4:
+        return 'VUS'
+    elif score >= 2:
+        return 'Likely Benign'
+    else:
+        return 'Benign'
+```
+
+**Report Section**:
+```markdown
+### 5. Pathogenicity Scoring
+
+#### Quantitative Assessment (0-10 Scale)
+
+| Component | Points | Max | Contribution | Rationale |
+|-----------|--------|-----|-------------|-----------|
+| **Gene Content** | 4.0 | 4 | 40% | KANSL1 (HI score 3), MAPT (HI score 2) |
+| **Dosage Sensitivity** | 2.5 | 3 | 25% | One definitive HI gene (KANSL1) |
+| **Population Frequency** | 2.0 | 2 | 20% | Absent from gnomAD SVs |
+| **Clinical Evidence** | 1.0 | 1 | 10% | ClinVar pathogenic match |
+| **Total Score** | **9.5** | 10 | 100% | |
+
+**Classification**: **Pathogenic** (★★★ High Confidence)
+
+**Interpretation**: Score of 9.5/10 indicates high confidence pathogenic SV. Deletion encompasses established haploinsufficient gene (KANSL1), absent from population databases, and matches known pathogenic ClinVar variant.
+
+#### Score Breakdown Visualization
+
+```
+Gene Content:        ████████████████████████████████████████ 4.0/4
+Dosage Sensitivity:  ██████████████████████████░░░░░░░░░░░░░ 2.5/3
+Population Freq:     ████████████████████████████████████████ 2.0/2
+Clinical Evidence:   ██████████████████████████████████████░░ 1.0/1
+                     ─────────────────────────────────────────
+Total:               ██████████████████████████████████████░░ 9.5/10
+```
+
+**Key Drivers of Pathogenicity**:
+1. KANSL1 haploinsufficiency (definitive evidence)
+2. Exact match to known pathogenic deletion
+3. Absence from population databases
+4. Phenotype consistency with Koolen-De Vries syndrome
+```
+
+---
+
+### Phase 6: Literature & Clinical Evidence
+
+**Goal**: Find case reports, functional studies, and clinical validation
+
+**Tools**:
+| Tool | Purpose | Coverage |
+|------|---------|----------|
+| `PubMed_search` | Peer-reviewed literature | Comprehensive |
+| `DECIPHER_search` | Patient case database | Developmental disorders |
+| `EuropePMC_search` | European literature | Additional coverage |
+
+**Search Strategies**:
+
+```python
+def comprehensive_literature_search(tu, genes, sv_type, phenotype):
+    """
+    Search literature for SV evidence.
+    """
+    # 1. Gene-specific searches
+    literature = []
+    for gene in genes:
+        # Dosage sensitivity literature
+        dosage_papers = tu.tools.PubMed_search(
+            query=f'"{gene}" AND (haploinsufficiency OR dosage sensitivity OR deletion syndrome)',
+            max_results=20
+        )
+
+        # Case reports
+        case_papers = tu.tools.PubMed_search(
+            query=f'"{gene}" AND deletion AND {phenotype}',
+            max_results=15
+        )
+
+        literature.append({
+            'gene': gene,
+            'dosage_papers': dosage_papers,
+            'case_reports': case_papers
+        })
+
+    # 2. SV-specific searches
+    if sv_type == 'DEL':
+        sv_papers = tu.tools.PubMed_search(
+            query=f'deletion AND {" AND ".join(genes[:3])} AND syndrome',
+            max_results=25
+        )
+
+    # 3. DECIPHER cases
+    decipher_cases = []
+    for gene in genes:
+        cases = tu.tools.DECIPHER_search(
+            query=gene,
+            search_type="gene"
+        )
+        decipher_cases.append(cases)
+
+    return {
+        'gene_literature': literature,
+        'sv_literature': sv_papers,
+        'decipher_cases': decipher_cases
+    }
+```
+
+**Report Section**:
+```markdown
+### 6. Literature & Clinical Evidence
+
+#### Key Publications
+
+| Study | Finding | Evidence Type | PMID |
+|-------|---------|---------------|------|
+| Koolen et al., 2006 | Described 17q21.31 microdeletion syndrome | Original description | 16222315 |
+| Koolen et al., 2008 | KANSL1 haploinsufficiency confirmed | Functional validation | 18394581 |
+| Zollino et al., 2012 | Phenotype characterization (n=52) | Clinical series | 22736773 |
+
+**Key Findings**:
+- 17q21.31 deletion is recurrent (mediated by LCRs)
+- KANSL1 haploinsufficiency is primary mechanism
+- Phenotype: ID (100%), hypotonia (95%), friendly demeanor (85%)
+- Penetrance: >95% for developmental features
+
+*Source: PubMed via `PubMed_search`*
+
+#### DECIPHER Patient Cases (n=45)
+
+**Phenotype Frequency in DECIPHER Cohort**:
+| Feature | Frequency | Match to Patient |
+|---------|-----------|------------------|
+| Intellectual disability | 45/45 (100%) | ✓ Yes |
+| Hypotonia | 42/45 (93%) | ✓ Yes |
+| Feeding difficulties | 38/45 (84%) | ✓ Yes |
+| Distinctive facies | 40/45 (89%) | ✓ Yes |
+| Friendly personality | 35/45 (78%) | Unknown |
+
+**Phenotype Match**: Patient phenotype highly consistent with DECIPHER cohort (4/4 assessable features present).
+
+**ACMG Code**: **PP4** (Supporting) - Patient's clinical features consistent with gene's known phenotype
+
+*Source: DECIPHER via `DECIPHER_search`*
+
+#### Functional Evidence for KANSL1 Dosage Sensitivity
+
+| Study | Model | Finding | PMID |
+|-------|-------|---------|------|
+| Koolen et al., 2012 | Patient cells | Reduced KANSL1 protein | 22736773 |
+| Zollino et al., 2015 | Mouse model | Kansl1+/- recapitulates phenotype | 25607366 |
+| Arbogast et al., 2017 | Zebrafish | kansl1 knockdown → developmental defects | 28666126 |
+
+**Strength of Evidence**: ★★★ (High) - Multiple independent studies confirm haploinsufficiency mechanism
+
+**ACMG Code**: **PS3_Moderate** - Well-established functional studies showing dosage sensitivity
+```
+
+---
+
+### Phase 7: ACMG-Adapted Classification
+
+**Goal**: Apply ACMG/ClinGen criteria adapted for SVs
+
+**SV-Specific ACMG Criteria**:
+
+### Pathogenic Evidence Codes
+
+| Code | Strength | Criteria | SV Application |
+|------|----------|----------|----------------|
+| **PVS1** | Very Strong | Null variant in HI gene | Complete deletion of HI gene |
+| **PS1** | Strong | Same SV as known pathogenic | ≥70% reciprocal overlap with ClinVar pathogenic |
+| **PS2** | Strong | De novo (maternity/paternity confirmed) | De novo SV in patient with matching phenotype |
+| **PS3** | Strong | Functional studies | Gene dosage effects demonstrated |
+| **PS4** | Strong | Case-control enrichment | SV enriched in cases vs controls |
+| **PM1** | Moderate | Critical region | Deletion of exons in HI gene |
+| **PM2** | Moderate | Absent from controls | Not in gnomAD SVs, DGV |
+| **PM3** | Moderate | Recessive: homozygous or compound het | Both alleles affected (rare for SVs) |
+| **PM4** | Moderate | Protein length change | In-frame deletion/duplication |
+| **PM5** | Moderate | Similar SVs pathogenic | Nearby SVs in ClinVar pathogenic |
+| **PM6** | Moderate | De novo (no confirmation) | De novo SV, phenotype consistent |
+| **PP1** | Supporting | Segregation in family | SV segregates with phenotype |
+| **PP2** | Supporting | Gene/pathway relevant | Genes in SV match phenotype |
+| **PP3** | Supporting | Computational evidence | Multiple predictors support haploinsufficiency |
+| **PP4** | Supporting | Phenotype consistent | Patient phenotype matches gene-disease |
+
+### Benign Evidence Codes
+
+| Code | Strength | Criteria | SV Application |
+|------|----------|----------|----------------|
+| **BA1** | Stand-Alone | MAF >5% | SV frequency >5% in gnomAD |
+| **BS1** | Strong | MAF too high for disease | SV frequency >1% |
+| **BS2** | Strong | Healthy adult with phenotype-associated genotype | SV in healthy individual (careful - reduced penetrance) |
+| **BS3** | Strong | Functional studies show no effect | No dosage sensitivity demonstrated |
+| **BS4** | Strong | Non-segregation | SV doesn't segregate with phenotype |
+| **BP1** | Supporting | Missense in gene without known LOF | N/A for SVs |
+| **BP2** | Supporting | Observed in trans with pathogenic | SV + pathogenic SNV = compound het (patient unaffected) |
+| **BP4** | Supporting | Computational evidence benign | Predictors suggest no haploinsufficiency |
+| **BP5** | Supporting | Found in case with alt cause | Phenotype explained by different variant |
+| **BP7** | Supporting | Synonymous with no splice effect | N/A for SVs |
+
+**Classification Algorithm** (ACMG SV Criteria):
+
+| Classification | Evidence Required |
+|----------------|-------------------|
+| **Pathogenic** | PVS1 + PS1; OR 2 Strong; OR 1 Strong + 3 Moderate |
+| **Likely Pathogenic** | 1 Very Strong + 1 Moderate; OR 1 Strong + 2 Moderate; OR 3 Moderate |
+| **VUS** | Criteria not met; OR conflicting evidence |
+| **Likely Benign** | 1 Strong + 1 Supporting; OR 2 Supporting |
+| **Benign** | BA1; OR BS1 + BS2; OR 2 Strong |
+
+**Implementation**:
+
+```python
+def apply_acmg_criteria(gene_content, dosage_data, frequency_data, clinical_data, inheritance):
+    """
+    Apply ACMG SV criteria and calculate classification.
+    """
+    evidence = {
+        'pathogenic': [],
+        'benign': []
+    }
+
+    # PVS1: Complete deletion of HI gene
+    hi_genes = [d for d in dosage_data if d['hi_score'] == '3']
+    if len(hi_genes) > 0 and len(gene_content['fully_contained']) > 0:
+        evidence['pathogenic'].append({
+            'code': 'PVS1',
+            'strength': 'Very Strong',
+            'rationale': f"Complete deletion of haploinsufficient gene(s): {', '.join(g['gene'] for g in hi_genes)}"
+        })
+
+    # PS1: Same as known pathogenic SV
+    if clinical_data.get('clinvar_pathogenic_match'):
+        evidence['pathogenic'].append({
+            'code': 'PS1',
+            'strength': 'Strong',
+            'rationale': f"≥70% overlap with ClinVar pathogenic SV: {clinical_data['clinvar_id']}"
+        })
+
+    # PS2: De novo with phenotype match
+    if inheritance == 'de_novo' and clinical_data.get('phenotype_match'):
+        evidence['pathogenic'].append({
+            'code': 'PS2',
+            'strength': 'Strong',
+            'rationale': "De novo occurrence in patient with consistent phenotype"
+        })
+
+    # PS3: Functional studies
+    if clinical_data.get('functional_evidence'):
+        evidence['pathogenic'].append({
+            'code': 'PS3',
+            'strength': 'Strong',
+            'rationale': "Well-established functional studies demonstrate dosage sensitivity"
+        })
+
+    # PM2: Absent from controls
+    if frequency_data.get('frequency') == 0 or frequency_data.get('frequency') is None:
+        evidence['pathogenic'].append({
+            'code': 'PM2',
+            'strength': 'Moderate',
+            'rationale': "Absent from gnomAD SV database and DGV"
+        })
+
+    # PP4: Phenotype consistent
+    if clinical_data.get('phenotype_consistent'):
+        evidence['pathogenic'].append({
+            'code': 'PP4',
+            'strength': 'Supporting',
+            'rationale': "Patient phenotype highly consistent with gene-disease association"
+        })
+
+    # BA1: Common variant
+    if frequency_data.get('frequency', 0) > 0.05:
+        evidence['benign'].append({
+            'code': 'BA1',
+            'strength': 'Stand-Alone',
+            'rationale': f"Frequency {frequency_data['frequency']:.3f} too high for rare disease"
+        })
+
+    # BS1: High frequency
+    if 0.01 < frequency_data.get('frequency', 0) <= 0.05:
+        evidence['benign'].append({
+            'code': 'BS1',
+            'strength': 'Strong',
+            'rationale': f"Frequency {frequency_data['frequency']:.3f} exceeds expected for disease"
+        })
+
+    # Calculate classification
+    classification = determine_classification(evidence)
+
+    return {
+        'evidence': evidence,
+        'classification': classification['class'],
+        'confidence': classification['confidence']
+    }
+
+def determine_classification(evidence):
+    """
+    Apply ACMG classification rules.
+    """
+    path = evidence['pathogenic']
+    ben = evidence['benign']
+
+    # Count evidence by strength
+    very_strong = len([e for e in path if e['strength'] == 'Very Strong'])
+    strong_path = len([e for e in path if e['strength'] == 'Strong'])
+    moderate_path = len([e for e in path if e['strength'] == 'Moderate'])
+    supporting_path = len([e for e in path if e['strength'] == 'Supporting'])
+
+    standalone_ben = len([e for e in ben if e['strength'] == 'Stand-Alone'])
+    strong_ben = len([e for e in ben if e['strength'] == 'Strong'])
+    supporting_ben = len([e for e in ben if e['strength'] == 'Supporting'])
+
+    # Benign criteria (takes precedence if strong)
+    if standalone_ben >= 1:
+        return {'class': 'Benign', 'confidence': '★★★'}
+    if strong_ben >= 2:
+        return {'class': 'Benign', 'confidence': '★★★'}
+    if strong_ben >= 1 and supporting_ben >= 1:
+        return {'class': 'Likely Benign', 'confidence': '★★☆'}
+    if supporting_ben >= 2:
+        return {'class': 'Likely Benign', 'confidence': '★★☆'}
+
+    # Pathogenic criteria
+    if very_strong >= 1 and strong_path >= 1:
+        return {'class': 'Pathogenic', 'confidence': '★★★'}
+    if strong_path >= 2:
+        return {'class': 'Pathogenic', 'confidence': '★★★'}
+    if very_strong >= 1 and moderate_path >= 1:
+        return {'class': 'Likely Pathogenic', 'confidence': '★★☆'}
+    if strong_path >= 1 and moderate_path >= 2:
+        return {'class': 'Likely Pathogenic', 'confidence': '★★☆'}
+    if strong_path >= 1 and moderate_path >= 1 and supporting_path >= 1:
+        return {'class': 'Likely Pathogenic', 'confidence': '★★☆'}
+    if moderate_path >= 3:
+        return {'class': 'Likely Pathogenic', 'confidence': '★☆☆'}
+
+    # Default to VUS
+    return {'class': 'VUS', 'confidence': '★☆☆'}
+```
+
+**Report Section**:
+```markdown
+### 7. ACMG-Adapted Classification
+
+#### Evidence Codes Applied
+
+**Pathogenic Evidence**:
+
+| Code | Strength | Rationale |
+|------|----------|-----------|
+| **PVS1** | Very Strong | Complete deletion of haploinsufficient gene (KANSL1, HI score 3) |
+| **PS1** | Strong | ≥95% overlap with ClinVar pathogenic deletion (VCV000012345) |
+| **PM2** | Moderate | Absent from gnomAD SV database (>10,000 genomes) |
+| **PP4** | Supporting | Patient phenotype consistent with Koolen-De Vries syndrome |
+
+**Benign Evidence**: None
+
+#### Evidence Summary
+
+| Pathogenic | Benign |
+|------------|--------|
+| 1 Very Strong (PVS1) | None |
+| 1 Strong (PS1) | |
+| 1 Moderate (PM2) | |
+| 1 Supporting (PP4) | |
+
+#### Classification: **PATHOGENIC** ★★★
+
+**Rationale**: Meets ACMG criteria for Pathogenic (1 Very Strong + 1 Strong). Complete deletion of established haploinsufficient gene (KANSL1) with exact match to known pathogenic deletion.
+
+**Confidence**: ★★★ (High) - Multiple independent lines of strong evidence
+
+#### Classification Certainty Factors
+
+✅ **Strengths**:
+- Exact match to well-characterized pathogenic deletion
+- Complete deletion of definitive HI gene (KANSL1)
+- Absent from population databases
+- Phenotype highly consistent with gene-disease
+
+⚠ **Limitations**:
+- None significant - this is a well-established pathogenic SV
+```
+
+---
+
+## Output Structure
+
+### Report File: `SV_analysis_report.md`
+
+```markdown
+# Structural Variant Analysis Report: [SV_IDENTIFIER]
+
+**Generated**: [Date] | **Analyst**: ToolUniverse SV Interpreter
+
+---
+
+## Executive Summary
+
+| Field | Value |
+|-------|-------|
+| **SV Type** | Deletion / Duplication / Inversion / Translocation |
+| **Coordinates** | chr17:44039927-44352659 (GRCh38) |
+| **Size** | 313 kb |
+| **Gene Content** | 2 genes fully contained, 0 partially disrupted |
+| **Classification** | Pathogenic / Likely Pathogenic / VUS / Likely Benign / Benign |
+| **Pathogenicity Score** | X.X / 10 |
+| **Confidence** | ★★★ / ★★☆ / ★☆☆ |
+| **Key Finding** | [One-sentence summary] |
+
+**Clinical Action**: [Required / Recommended / None]
+
+---
+
+## 1. SV Identity & Classification
+
+{SV type, coordinates, size, breakpoint precision, inheritance}
+
+---
+
+## 2. Gene Content Analysis
+
+### 2.1 Fully Contained Genes
+{Table of genes with functions, disease associations}
+
+### 2.2 Partially Disrupted Genes
+{Genes with breakpoints, domains affected}
+
+### 2.3 Flanking Genes
+{Genes near breakpoints, position effect risk}
+
+---
+
+## 3. Dosage Sensitivity Assessment
+
+### 3.1 Haploinsufficient Genes
+{ClinGen HI scores, pLI, evidence}
+
+### 3.2 Triplosensitive Genes
+{ClinGen TS scores, duplication syndromes}
+
+### 3.3 Non-Dosage-Sensitive Genes
+{Genes without established dosage effects}
+
+---
+
+## 4. Population Frequency Context
+
+### 4.1 ClinVar Matches
+{Known pathogenic/benign SVs}
+
+### 4.2 gnomAD SV Database
+{Population frequencies}
+
+### 4.3 DECIPHER Patient Cases
+{Similar SVs, phenotype matching}
+
+---
+
+## 5. Pathogenicity Scoring
+
+### 5.1 Quantitative Assessment
+{0-10 score with breakdown}
+
+### 5.2 Score Components
+{Gene content, dosage, frequency, clinical}
+
+---
+
+## 6. Literature & Clinical Evidence
+
+### 6.1 Key Publications
+{Functional studies, case series}
+
+### 6.2 DECIPHER Cohort Analysis
+{Phenotype frequencies, matching}
+
+### 6.3 Functional Evidence
+{Gene dosage studies}
+
+---
+
+## 7. ACMG-Adapted Classification
+
+### 7.1 Evidence Codes Applied
+{Pathogenic and benign codes with rationale}
+
+### 7.2 Classification
+{Final classification with confidence}
+
+### 7.3 Certainty Factors
+{Strengths and limitations}
+
+---
+
+## 8. Clinical Recommendations
+
+### 8.1 For Affected Individual
+{Testing, management, surveillance}
+
+### 8.2 For Family Members
+{Cascade testing, genetic counseling}
+
+### 8.3 Reproductive Considerations
+{Recurrence risk, prenatal testing}
+
+---
+
+## 9. Limitations & Uncertainties
+
+{Missing data, conflicting evidence, knowledge gaps}
+
+---
+
+## Data Sources
+
+{All tools and databases queried with results}
+```
+
+---
+
+## Evidence Grading System
+
+| Symbol | Confidence | Criteria |
+|--------|------------|----------|
+| ★★★ | High | ClinGen definitive, ClinVar expert reviewed, multiple independent studies |
+| ★★☆ | Moderate | ClinGen strong/moderate, single good study, DECIPHER cohort support |
+| ★☆☆ | Limited | Computational predictions only, case reports, emerging evidence |
+
+---
+
+## Special Scenarios
+
+### Scenario 1: Recurrent Microdeletion Syndrome
+
+**Additional considerations**:
+- Check for recurrence mechanism (LCRs, NAHR)
+- Look for founder effects
+- Population-specific frequencies
+- Incomplete penetrance
+- Variable expressivity
+
+**Example**: 22q11.2 deletion, 17q21.31 deletion (Koolen-De Vries)
+
+### Scenario 2: Balanced Translocation (No Gene Disruption)
+
+**Assessment approach**:
+- If no genes disrupted: Likely benign (in most cases)
+- Check for cryptic imbalances
+- Consider position effects (rare)
+- Reproductive risk (unbalanced offspring)
+
+**Classification**: Usually VUS or Likely Benign unless offspring affected
+
+### Scenario 3: Complex Rearrangement
+
+**Analysis strategy**:
+- Break down into component SVs
+- Assess each breakpoint independently
+- Look for chromothripsis pattern
+- Consider cumulative gene dosage effects
+- Check for DNA repair defects
+
+### Scenario 4: Small In-Frame Deletion/Duplication
+
+**Special considerations**:
+- May not cause haploinsufficiency
+- Check if critical domain affected
+- Look for similar variants in ClinVar
+- Consider protein structural impact
+- May need functional studies
+
+---
+
+## Quantified Minimums
+
+| Section | Requirement |
+|---------|-------------|
+| Gene content | All genes in SV region annotated |
+| Dosage sensitivity | ClinGen scores for all genes (if available) |
+| Population frequency | Check gnomAD SV + ClinVar + DGV |
+| Literature search | ≥2 search strategies (PubMed + DECIPHER) |
+| ACMG codes | All applicable codes listed |
+
+---
+
+## Tools Reference
+
+### Core Tools for SV Analysis
+
+| Tool | Purpose | Required? |
+|------|---------|-----------|
+| `ClinGen_search_dosage_sensitivity` | HI/TS scores | **Required** |
+| `ClinGen_search_gene_validity` | Gene-disease validity | **Required** |
+| `ClinVar_search_variants` | Known pathogenic/benign SVs | **Required** |
+| `DECIPHER_search` | Patient cases, phenotypes | Highly recommended |
+| `Ensembl_lookup_gene` | Gene coordinates, structure | **Required** |
+| `OMIM_search`, `OMIM_get_entry` | Gene-disease associations | **Required** |
+| `DisGeNET_search_gene` | Additional disease associations | Recommended |
+| `PubMed_search` | Literature evidence | Recommended |
+| `Gene_Ontology_get_term_info` | Gene function | Supporting |
+
+---
+
+## Report File Naming
+
+```
+SV_analysis_[TYPE]_chr[CHR]_[START]_[END]_[GENES].md
+
+Examples:
+SV_analysis_DEL_chr17_44039927_44352659_KANSL1_MAPT.md
+SV_analysis_DUP_chr22_17400000_17800000_TBX1.md
+SV_analysis_INV_chr11_2100000_2400000_complex.md
+```
+
+---
+
+## Clinical Recommendations Framework
+
+### For Pathogenic/Likely Pathogenic SVs
+
+| SV Type | Recommendations |
+|---------|-----------------|
+| **Deletion (HI gene)** | Genetic counseling, cascade testing, phenotype-specific surveillance |
+| **Duplication (TS gene)** | Same as deletion; check for dosage-specific syndrome |
+| **Translocation (disruption)** | Assess both breakpoints, consider reproductive counseling |
+| **Complex** | Multidisciplinary evaluation, research enrollment |
+
+### For VUS
+
+| Action | Details |
+|--------|---------|
+| Clinical management | Base on phenotype, not genotype |
+| Follow-up | Reinterpret in 1-2 years or when phenotype evolves |
+| Research | Functional studies if research-grade samples available |
+| Family studies | Segregation analysis can reclassify |
+
+### For Benign/Likely Benign
+
+| Action | Details |
+|--------|---------|
+| Clinical | Not expected to cause rare disease |
+| Family | No cascade testing needed (unless recurrent/reproductive risk) |
+| Reproductive | Balanced translocation carriers may have offspring risk |
+
+---
+
+## When NOT to Use This Skill
+
+- **Single nucleotide variants (SNVs)** → Use `tooluniverse-variant-interpretation` skill
+- **Small indels (<50 bp)** → Use variant interpretation skill
+- **Somatic variants in cancer** → Different framework needed
+- **Mitochondrial variants** → Specialized interpretation required
+- **Repeat expansions** → Different mechanism
+
+Use this skill for **structural variants ≥50 bp** requiring dosage sensitivity assessment and ACMG-adapted classification.
+
+---
+
+## See Also
+
+- `EXAMPLES.md` - Sample SV interpretations
+- `README.md` - Quick start guide
+- `tooluniverse-variant-interpretation` - For SNVs and small indels
+- ClinGen Dosage Sensitivity Map: https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/
+- ACMG SV Guidelines: Riggs et al., Genet Med 2020 (PMID: 31690835)