rs775130589

Variant names:

• chr15-42410897-C-CA
• rs775130589
• NM_000070.3:c.2279dupA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PVS1 PP4 PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.2279dup p.(Asn760LysfsTer5) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 22/24, 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 four individuals with LGMD (PMID:18055493, 30564623; LOVD CAPN3_000399), including in trans with a variant not yet curated by the VCEP and considered VUS in two cases (0.5 pts) (PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The highest population minor allele frequency of this variant is 0.000008797 (1/113680 exome alleles) in the European (non-Finnish) population in gnomAD v2.1.1, which is less than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (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_Supporting, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511816/MONDO:0015152/187

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 6.22

Genes affected

CAPN3 (HGNC:1480): (calpain 3) 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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2279dupA	p.Asn760LysfsTer5	frameshift_variant	Exon 22 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2279dupA	p.Asn760LysfsTer5	frameshift_variant	Exon 22 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.284dupA	p.Asn95LysfsTer5	frameshift_variant	Exon 9 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.284dupA	p.Asn95LysfsTer5	frameshift_variant	Exon 9 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.284dupA	p.Asn95LysfsTer5	frameshift_variant	Exon 10 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.284dupA	p.Asn95LysfsTer5	frameshift_variant	Exon 9 of 11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.182dupA	p.Asn61LysfsTer5	frameshift_variant	Exon 9 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2715dupA		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2715dupA		3_prime_UTR_variant	Exon 24 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251396 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461680 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

May 25, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a pathogenic variant (p.Arg490Trp) in a patient in the published literature with Limb-girdle muscular dystrophy, but it is unknown whether the variants occurred on the same allele (in cis) or on different alleles (in trans) (Groen et al., 2007); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18055493) -

Jul 01, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2279dupA CAPN3 pathogenic variant has been reported in individuals with LGMD2A1,2 and is of a type expected to cause disease. 1. Groen et al. Brain. 2007 Dec;130(Pt 12):3237-49. 2. www.lovd.nl/CAPN3 AKT 7-1-16 -

Oct 12, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:2

Jul 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn760Lysfs*5) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive limb girdle muscular dystrophy (PMID: 18055493). This variant is also known as c.2278insA. ClinVar contains an entry for this variant (Variation ID: 289082). For these reasons, this variant has been classified as Pathogenic. -

Nov 09, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Jan 09, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 09, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000070.3: c.2279dup p.(Asn760LysfsTer5) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 22/24, 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 four individuals with LGMD (PMID: 18055493, 30564623; LOVD CAPN3_000399), including in trans with a variant not yet curated by the VCEP and considered VUS in two cases (0.5 pts) (PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The highest population minor allele frequency of this variant is 0.000008797 (1/113680 exome alleles) in the European (non-Finnish) population in gnomAD v2.1.1, which is less than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (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_Supporting, PP4, PM2_Supporting. -

CAPN3-related disorder Pathogenic:1

Apr 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CAPN3 c.2279dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn760Lysfs*5). This variant was reported in the compound heterozygous state in an individual with limb-girdle muscular dystrophy 2A (Groen et al 2007. PubMed ID: 18055493). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-42703095-C-CA). Frameshift variants in CAPN3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs775130589; hg19: chr15-42703095;