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 (High/Moderate/Limited)
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

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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

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Workflow Overview

Phase 1: SV IDENTITY & CLASSIFICATION
  Normalize coordinates (hg19/hg38), determine type (DEL/DUP/INV/TRA/CPX),
  calculate size, assess breakpoint precision

Phase 2: GENE CONTENT ANALYSIS
  Identify fully contained genes, partially disrupted genes (breakpoint within),
  flanking genes (within 1 Mb), annotate function and disease associations

Phase 3: DOSAGE SENSITIVITY ASSESSMENT
  ClinGen HI/TS scores, pLI scores, OMIM inheritance patterns,
  gene-disease validity levels

Phase 4: POPULATION FREQUENCY CONTEXT
  gnomAD SV database, ClinVar known SVs, DECIPHER patient cases,
  reciprocal overlap calculation (>=70% = same SV)

Phase 5: PATHOGENICITY SCORING
  Quantitative 0-10 scale: gene content (40%), dosage sensitivity (30%),
  population frequency (20%), clinical evidence (10%)

Phase 6: LITERATURE & CLINICAL EVIDENCE
  PubMed searches, DECIPHER cohort analysis, functional evidence

Phase 7: ACMG-ADAPTED CLASSIFICATION
  Apply SV-specific evidence codes, calculate final classification,
  generate clinical recommendations

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Phase 1: SV Identity & Classification

Goal: Standardize SV notation and classify type.

Capture: chromosome(s), coordinates (start/end in hg19/hg38), SV size, SV type (DEL/DUP/INV/TRA/CPX), breakpoint precision, inheritance pattern (de novo/inherited/unknown).

For SV type definitions, scoring tables, and ACMG code details, see CLASSIFICATION_GUIDE.md.

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Phase 2: Gene Content Analysis

Goal: Annotate all genes affected by the SV.

Tools:

Tool	Purpose
Ensembl_lookup_gene	Gene structure, coordinates, exons
NCBI_gene_search	Official symbol, aliases, description
Gene_Ontology_get_term_info	Biological process, molecular function
OMIM_search, OMIM_get_entry	Disease associations, inheritance
DisGeNET_search_gene	Gene-disease association scores

Classify genes as: fully contained (entire gene in SV), partially disrupted (breakpoint within gene), or flanking (within 1 Mb of breakpoints).

For implementation pseudocode, see ANALYSIS_PROCEDURES.md Phase 2.

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Phase 3: Dosage Sensitivity Assessment

Goal: Determine if affected genes are dosage-sensitive.

Tools:

Tool	Purpose
ClinGen_search_dosage_sensitivity	HI/TS scores (0-3, gold standard)
ClinGen_search_gene_validity	Gene-disease validity level
gnomad_search	pLI scores for LoF intolerance
DECIPHER_search	Developmental disorder cases
OMIM_get_entry	Inheritance pattern (AD suggests dosage sensitivity)

Key thresholds: ClinGen HI/TS score 3 = definitive dosage sensitivity. pLI >= 0.9 = likely haploinsufficient. See CLASSIFICATION_GUIDE.md for full score interpretation tables.

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Phase 4: Population Frequency Context

Goal: Determine if SV is common (likely benign) or rare (supports pathogenicity).

Tools:

Tool	Purpose
gnomad_search	Population SV frequencies
ClinVar_search_variants	Known pathogenic/benign SVs
DECIPHER_search	Patient SVs with phenotypes

Key thresholds: >=1% = BA1 (benign). 0.1-1% = BS1 (strong benign). <0.01% = PM2 (supporting pathogenic). Use >=70% reciprocal overlap to define "same" SV.

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Phase 5: Pathogenicity Scoring

Goal: Quantitative pathogenicity assessment on 0-10 scale.

Four components weighted: gene content (40%), dosage sensitivity (30%), population frequency (20%), clinical evidence (10%).

Score mapping: 9-10 = Pathogenic, 7-8 = Likely Pathogenic, 4-6 = VUS, 2-3 = Likely Benign, 0-1 = Benign.

For detailed scoring breakdowns and implementation, see CLASSIFICATION_GUIDE.md and ANALYSIS_PROCEDURES.md Phase 5.

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Phase 6: Literature & Clinical Evidence

Goal: Find case reports, functional studies, and clinical validation.

Tools:

Tool	Purpose
PubMed_search	Peer-reviewed literature
EuropePMC_search	European literature (additional coverage)
DECIPHER_search	Patient case database

Search strategies: gene-specific dosage sensitivity papers, SV-specific case reports, DECIPHER cohort phenotype analysis. See ANALYSIS_PROCEDURES.md Phase 6.

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Phase 7: ACMG-Adapted Classification

Goal: Apply ACMG/ClinGen criteria adapted for SVs.

Key pathogenic codes: PVS1 (deletion of HI gene), PS1 (matches known pathogenic SV), PS2 (de novo), PM2 (absent from controls), PP4 (phenotype match).

Key benign codes: BA1 (MAF >5%), BS1 (MAF >1%), BS3 (no functional effect).

Classification rules: Pathogenic = PVS1+PS1 or 2 Strong. Likely Pathogenic = 1 Very Strong + 1 Moderate, or 3 Moderate. VUS = criteria not met. Likely Benign = 1 Strong + 1 Supporting. Benign = BA1, or 2 Strong benign.

For complete evidence code tables and classification algorithm, see CLASSIFICATION_GUIDE.md.

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Output

Create report using the template in REPORT_TEMPLATE.md. Name files as:

SV_analysis_[TYPE]_chr[CHR]_[START]_[END]_[GENES].md

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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

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Tools Reference

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

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When NOT to Use This Skill

• Single nucleotide variants (SNVs) - Use tooluniverse-variant-interpretation
• 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.

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Reference Files

• EXAMPLES.md - Sample SV interpretations with worked examples
• CLASSIFICATION_GUIDE.md - ACMG criteria tables, scoring system, evidence codes, special scenarios, clinical recommendations
• REPORT_TEMPLATE.md - Full report template with section structure and file naming
• ANALYSIS_PROCEDURES.md - Detailed implementation pseudocode for each phase

External References

• ClinGen Dosage Sensitivity Map: https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/
• ACMG SV Guidelines: Riggs et al., Genet Med 2020 (PMID: 31690835)
• tooluniverse-variant-interpretation - For SNVs and small indels