Structural variant (SV) clinical interpretation: deletions, duplications, inversions, translocations, complex rearrangements. Applies ACMG-adapted criteria with ClinGen HI/TS dosage scores, gnomAD frequencies, and ClinVar evidence. Produces 5-tier classification with explicit per-criterion evidence.

COMPUTE, DON'T DESCRIBE When analysis requires computation (statistics, data processing, scoring, enrichment), write and run Python code via Bash. Don't describe what you would do — execute it and report actual results. Use ToolUniverse tools to retrieve data, then Python (pandas, scipy, statsmodels, matplotlib) to analyze it. Structural Variant Analysis Workflow Systematic analysis of structural variants (deletions, duplications, inversions, translocations, complex rearrangements) for clinical genomics interpretation using ACMG adapted criteria. LOOK UP DON'T GUESS Always retrieve ClinGen HI/TS scores, gnomAD frequencies, and ClinVar evidence from tools. Do not infer dosage sensitivity from gene function alone. 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. 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 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 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 GO get term details 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: 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) GO get term details 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

tooluniverse-structural-variant-analysis