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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 :
- Report-first approach - Create SV_analysis_report.md FIRST, then populate progressively
- ACMG-style classification - Pathogenic/Likely Pathogenic/VUS/Likely Benign/Benign with explicit evidence
- Evidence grading - Grade all findings by confidence level (High/Moderate/Limited)
- Dosage sensitivity critical - Gene dosage effects drive SV pathogenicity
- Breakpoint precision matters - Exact gene disruption vs dosage-only effects
- Population context essential - gnomAD SVs for frequency assessment
- 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
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
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
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.
Phase 2: Gene Content Analysis
Goal : Annotate all genes affected by the SV.
Tools :
| Tool | Purpose |
|---|
ensembl_lookup_gene | Gene structure, coordinates, exons |
NCBIGene_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.
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_variants | 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.
Phase 4: Population Frequency Context
Goal : Determine if SV is common (likely benign) or rare (supports pathogenicity).
Tools :
| Tool | Purpose |
|---|
gnomad_search_variants | 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.
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.
Phase 6: Literature & Clinical Evidence
Goal : Find case reports, functional studies, and clinical validation.
Tools :
| Tool | Purpose |
|---|
PubMed_search_articles | Peer-reviewed literature |
EuropePMC_search_articles | 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.
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.
Output
Create report using the template in REPORT_TEMPLATE.md. Name files as:
SV_analysis_[TYPE]_chr[CHR]_[START]_[END]_[GENES].md
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
| 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 |
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.
Reference Files
EXAMPLES.md - Sample SV interpretations with worked examplesCLASSIFICATION_GUIDE.md - ACMG criteria tables, scoring system, evidence codes, special scenarios, clinical recommendationsREPORT_TEMPLATE.md - Full report template with section structure and file namingANALYSIS_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
Weekly Installs
142
Repository
mims-harvard/to…universe
GitHub Stars
1.2K
First Seen
Feb 12, 2026
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