rs1555423217

chr15-42410981-TAG-TTCATCT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000070.3(CAPN3):c.2362_2363delinsTCATCT(p.Arg788SerfsTer14) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R788R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 5.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-42410982-AG-TCATCT is Pathogenic according to our data. Variant chr15-42410982-AG-TCATCT is described in ClinVar as [Pathogenic]. Clinvar id is 17618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.2362_2363delinsTCATCT	p.Arg788SerfsTer14	frameshift_variant	22/24	ENST00000397163.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.2362_2363delinsTCATCT	p.Arg788SerfsTer14	frameshift_variant	22/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 18, 2019	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2022	Frameshift variant predicted to result in protein truncation, as the last 34 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18337726, 10330340, 22194990, 16607617, 18055493, 15757244, 28615891, 9150160, 25900067, 9762961, 12461690, 17236769, 7720071, 16344536, 18563459, 21984748, 28103310, 31011535, 30919934, 31127727, 35741838, 15689361, 30564623) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 02, 2021	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2006	- -
not provided, no classification provided	literature only	GeneReviews	-	Pathogenic variant most likely the result of a founder effect followed by genetic isolation in populations in Guipuzcoa province in the Basque country of Spain, and in Brazil, [Urtasun et al 1998, de Paula et al 2002]. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 19, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	This sequence change creates a premature translational stop signal (p.Arg788Serfs*14) in the CAPN3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the CAPN3 protein. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 18563459, 21984748, 22194990). This variant is also known as 2362AG->TCATCT. ClinVar contains an entry for this variant (Variation ID: 17618). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 14, 2023

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 31, 2023

Variant summary: CAPN3 c.2362_2363delinsTCATCT (p.Arg788SerfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251342 control chromosomes (gnomAD). c.2362_2363delinsTCATCT has been reported in the literature in several homozygous- and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Richard_1997, de Paula_2002, Saenz_2005), where muscle biopsy samples derived from multiple homozygote patients demonstrated complete- or partial loss of calpain (see e.g. de Paula_2002, Saenz_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

Myositis, eosinophilic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555423217; hg19: chr15-42703180;