CAPN3

Chr 15ADAR

calpain 3

Also known as: CANP3, CANPL3, LGMD2, LGMD2A, LGMDD4, LGMDR1, nCL-1, p94

NCBI Gene: 825 ENSG00000092529 UniProt: P20807 OMIM: 114240

The protein is a muscle-specific calpain that functions as an intracellular protease and specifically binds to titin. Mutations cause limb-girdle muscular dystrophy with both autosomal recessive (type 2A/LGMDR1) and autosomal dominant (type 4/LGMDD4) inheritance patterns. The predicted mechanism involves gain-of-function effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.962 OMIM phenotypes

VCEP Guidelines: Limb Girdle Muscular DystrophyReleased

ClinGen Panel

Clinical Summary— CAPN3

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Gene-Disease Validity (ClinGen)

autosomal recessive limb-girdle muscular dystrophy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.96LOEUF

pLI 0.000

Z-score 1.75

OE 0.73 (0.56–0.96)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.03Z-score

OE missense 1.00 (0.93–1.08)

469 obs / 467.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.73 (0.56–0.96)

0≤0.351.4

Missense OE?1.00 (0.93–1.08)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 36 / 49.2Missense obs/exp: 469 / 467.0Syn Z: -1.63

This gene — mechanism propensity

0.6743th %ile

GOF

0.73top 25%

LOF

0.2776th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNMoreover, the D705G mutation had a dominant negative effect on endogenous CAPN3 when expressed on a WT background.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References