rs863224966

Variant names:

• chr15-42390034-GATA-CTT
• rs863224966
• NM_000070.3:c.883_886delGATAinsCTT

Your query was ambiguous. Multiple possible variants found:

• chr15-42390033-GGATA-GCTT
• chr15-42390033-GGATA-GGATAGATA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP1_Moderate PP4_Moderate PVS1 PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.883_886delinsCTT p.(Asp295LeufsTer57) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 8/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least 4 unrelated patients with clinical signs of LGMD (PMID:16141003, 15733273, 17994539, 16650086, 15689361, 30919934), including in a homozygous state in one individual without reported familial consanguinity (0.5 pts, PMID:1614100; PM3_Supporting). This variant has also been reported to co-segregate with autosomal recessive LGMD in 3 affected members of a single family (PMID:16141003; PP1_Moderate). In addition, at least one of the patients with this variant and a second presumed diagnostic CAPN3 variant had a clinical diagnosis of LGMD and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PP4_Moderate, capped with PP1_Moderate; PMID:16650086, 15689361). This variant is absent from gnomAD v4.1.0 (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; 06/03/2025): PVS1, PM3_Supporting, PP1_Moderate, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA347485/MONDO:0015152/187

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 5.52
• Publications: 1 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 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.
• PP1: 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.883_886delGATAinsCTT	p.Asp295LeufsTer57	frameshift_variant, missense_variant	Exon 6 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.883_886delGATAinsCTT	p.Asp295LeufsTer57	frameshift_variant, missense_variant	Exon 6 of 23		NP_077320.1
CAPN3	NM_173087.2	c.801+938_801+941delGATAinsCTT		intron_variant	Intron 5 of 20		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.883_886delGATAinsCTT	p.Asp295LeufsTer57	frameshift_variant, missense_variant	Exon 6 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*679_*682delGATAinsCTT		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*679_*682delGATAinsCTT		3_prime_UTR_variant	Exon 10 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

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

Dec 26, 2024

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.Asp295Leufs*57) 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 present in population databases (rs764874721, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16141003, 16650086, 17994539, 22057634). This variant is also known as c.[883_884GA>CT; 887delA]. For these reasons, this variant has been classified as Pathogenic. -

Aug 22, 2012

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Apr 25, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.883_886delGATAinsCTT variant has been previously reported in multiple individuals with suspected LGMD who had absent calpain-3 protein on western blot analysis (Todorova et al., 2005; Krahn et al., 2006; Guglieri et al., 2008); 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: 15733273, 16141003, 17994539, 30028523, 30919934, 16650086, 15689361, 26404900, 31788660) -

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

Jun 22, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Jan 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jun 03, 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.883_886delinsCTT p.(Asp295LeufsTer57) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 8/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least 4 unrelated patients with clinical signs of LGMD (PMID: 16141003, 15733273, 17994539, 16650086, 15689361, 30919934), including in a homozygous state in one individual without reported familial consanguinity (0.5 pts, PMID: 1614100; PM3_Supporting). This variant has also been reported to co-segregate with autosomal recessive LGMD in 3 affected members of a single family (PMID: 16141003; PP1_Moderate). In addition, at least one of the patients with this variant and a second presumed diagnostic CAPN3 variant had a clinical diagnosis of LGMD and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PP4_Moderate, capped with PP1_Moderate; PMID: 16650086, 15689361). This variant is absent from gnomAD v4.1.0 (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; 06/03/2025): PVS1, PM3_Supporting, PP1_Moderate, PP4_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs863224966; hg19: chr15-42682232;