tooluniverse-structural-variant-analysis

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.

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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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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:

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