CAPN3 p.Lys613fs
c.1838del · rs1555422832 · VCV554906
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PM2_Supporting PVS1 PP4 PM3
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.1838del p.(Lys613ArgfsTer49) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 17/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three individuals with features of limb girdle muscular dystrophy (PMID: 16607617, 18055493, ClinVar SCV000953543.3 internal data communication), including confirmed in trans with a pathogenic variant (c.1079G>A p.(Trp360Ter), 1.0 pt, ClinVar SCV000953543.3 internal data communication) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy or showed progressive limb girdle muscle weakness (PP4). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 16 of 24 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 3.3 | GERP 0.74, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,246 |
| European (non-Finnish)grpmax | 0.000593% | 168,548 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- CAPN3
- Protein
- p.Lys613fs
- Coding
- c.1838del
- MANE Select
- NM_000070
- dbSNP
- rs1555422832
- Type
- Deletion
- Location
- chr15:42408247 (GRCh38)
- Gene constraint
- LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 79.18 · 5 PDB
- Residue 613
- the 'linker' region; the 'disordered' region
Similar variants
- CAPN3 p.Lys613Arg Uncertain significance ★★ ⚠ same residue
- CAPN3 p.Lys613= Likely benign ★ same residue
- CAPN3 c.1194-2del Pathogenic ★★★ same condition
- CAPN3 p.Asp764fs Pathogenic ★★★ same condition
- CAPN3 p.Gln660_Ile661insTer Pathogenic ★★★ same condition
- CAPN3 p.Glu582fs Pathogenic ★★★ same condition
- CAPN3 p.Gly441fs Pathogenic ★★★ same condition
- CAPN3 p.Leu74fs Likely pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/capn3-p-lys613fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown