COMPUTE, DON'T DESCRIBE

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

SV Pathogenicity Reasoning (Start Here)

Before any tool call, apply this reasoning to frame the analysis:

SV pathogenicity depends on what the SV disrupts. A deletion removing an entire gene is likely pathogenic if the gene is haploinsufficient. A duplication is pathogenic if the gene is dosage-sensitive. An inversion is pathogenic only if it disrupts a coding region or regulatory element at the breakpoint.

Work through these questions in order:

1. What type is the SV, and what disruption mechanism does it cause?

• Deletion: loss of one copy. Pathogenic if any contained gene is haploinsufficient (ClinGen HI score 3, pLI >= 0.9). A deletion of a dosage-insensitive gene in a gene-dense region may be benign even if large.
• Duplication: gain of one copy. Pathogenic if any contained gene is dosage-sensitive (ClinGen TS score 3). Duplications can also disrupt gene regulation if tandem (disrupts reading frame at junction) or if they separate a gene from its enhancer.
• Inversion: no copy number change. Pathogenic only at the breakpoints: if one breakpoint falls within an exon (truncation) or separates a gene from its regulatory element. Inversions entirely within gene-poor, regulatory-poor regions are often benign.
• Translocation: pathogenic if a breakpoint disrupts a coding region or creates a pathogenic fusion gene. Balanced translocations in parents of affected children warrant special scrutiny.
• Complex rearrangements: assess each segment and each breakpoint independently.

2. Is the disrupted gene dosage-sensitive?

• ClinGen HI score 3 = definitive haploinsufficiency (deletion of this gene is pathogenic)
• ClinGen HI score 2 = likely haploinsufficient
• pLI >= 0.9 = strong LoF intolerance (supporting haploinsufficiency)
• ClinGen TS score 3 = definitive triplosensitivity (duplication is pathogenic)
• If no ClinGen data: use OMIM inheritance (autosomal dominant = often dosage-sensitive) as weaker evidence

3. Does the population frequency contextualize the SV?

• =1% frequency in gnomAD SV = BA1 (likely benign unless phenotype is extreme)

• <0.01% = supports pathogenicity (PM2)
• Present in unaffected parents = weak evidence against pathogenicity, but not conclusive

4. Is there clinical precedent?

• Identical SV in ClinVar as Pathogenic/Likely Pathogenic = strong evidence (PS1)
• De novo occurrence = strong evidence for pathogenicity (PS2)
• Phenotype match to known gene-disease association = supporting evidence (PP4)

Document this reasoning before computing the final score.

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:

• 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:

• 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
• OMIM_get_entry - inheritance pattern (AD suggests dosage sensitivity)

Interpret scores using the reasoning above. ClinGen HI/TS score 3 = definitive; score 2 = likely; score 1 = little evidence; score 0 = no evidence. Do not equate AD inheritance with haploinsufficiency without ClinGen support.

Phase 4: Population Frequency Context

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

Tools:

• gnomad_search_variants - population SV frequencies
• ClinVar_search_variants - known pathogenic/benign SVs
• ClinGen_search_dosage_sensitivity - patient SVs with phenotypes

Use >=70% reciprocal overlap to define "same" SV for comparison. A frequency >=1% triggers BA1 unless there is very strong clinical evidence to override.

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:

• PubMed_search_articles - peer-reviewed literature
• EuropePMC_search_articles - additional coverage
• ClinGen_search_dosage_sensitivity - patient case database

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

Phase 7: ACMG-Adapted Classification

Goal: Apply ACMG/ClinGen criteria adapted for SVs and generate a final classification with explicit evidence summary.

The LLM knows the ACMG criteria codes and combination rules. Apply them to the evidence gathered in Phases 1-6. Key points to verify with tool data:

• PVS1 applies to deletions of genes with ClinGen HI score >= 2 or pLI >= 0.9
• PS2 requires confirmed de novo status (check parental genotypes if available)
• PM2 requires absence from population databases at >=70% reciprocal overlap

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

Required Tools Reference

• ClinGen_search_dosage_sensitivity - HI/TS scores (required for all deletions/duplications)
• ClinGen_search_gene_validity - gene-disease validity (required)
• ClinVar_search_variants - known pathogenic/benign SVs (required)
• ensembl_lookup_gene - gene coordinates, structure (required)
• OMIM_search, OMIM_get_entry - gene-disease associations (required)
• gnomad_search_variants - population frequency and pLI (required)
• DisGeNET_search_gene - additional disease associations (recommended)
• PubMed_search_articles - literature evidence (recommended)
• Gene_Ontology_get_term_info - gene function (supporting)

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 examples
• CLASSIFICATION_GUIDE.md - ACMG criteria, 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