rs863224966

Positions:

• chr15-42390033-GGATA-GCTT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000397163.8(CAPN3):​c.883_886delinsCTT​(p.Asp295LeufsTer57) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D295D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 ENST00000397163.8 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.52

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-42390034-GATA-CTT is Pathogenic according to our data. Variant chr15-42390034-GATA-CTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.883_886delinsCTT	p.Asp295LeufsTer57	frameshift_variant	6/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.883_886delinsCTT	p.Asp295LeufsTer57	frameshift_variant	6/23		NP_077320.1
CAPN3	NM_173087.2	c.801+938_801+941delinsCTT		intron_variant			NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.883_886delinsCTT	p.Asp295LeufsTer57	frameshift_variant	6/24	1	NM_000070.3	ENSP00000380349	P2

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/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2023	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. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2018	- -

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

Pathogenic, flagged submission

clinical testing

Baylor Genetics

Jun 22, 2022

- -

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: rs863224966; hg19: chr15-42682232;