15-42390033-GGATA-GCTT

Variant names:

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

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:8
• 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):

• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
• limb-girdle muscular dystrophy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.883_886delGATAinsCTT	p.Asp295LeufsTer57	frameshift missense	Exon 6 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.883_886delGATAinsCTT	p.Asp295LeufsTer57	frameshift missense	Exon 6 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.801+938_801+941delGATAinsCTT		intron	N/A	NP_775110.1	P20807-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.883_886delGATAinsCTT	p.Asp295LeufsTer57	frameshift missense	Exon 6 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.883_886delGATAinsCTT	p.Asp295LeufsTer57	frameshift missense	Exon 6 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.801+938_801+941delGATAinsCTT		intron	N/A	ENSP00000183936.4	P20807-2

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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)
1	-	-	Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

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;