NM_000070.3:c.1043delG

Variant names:

• chr15-42394267-AG-A
• rs781013226
• NM_000070.3:c.1043delG

Variant summary

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

The NM_000070.3(CAPN3):​c.1043delG​(p.Gly348ValfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000834 in 1,558,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.35

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-42394267-AG-A is Pathogenic according to our data. Variant chr15-42394267-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 286813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42394267-AG-A is described in Lovd as [Pathogenic]. Variant chr15-42394267-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1043delG	p.Gly348ValfsTer4	frameshift_variant	Exon 8 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1043delG	p.Gly348ValfsTer4	frameshift_variant	Exon 8 of 23		NP_077320.1
CAPN3	NM_173087.2	c.899delG	p.Gly300ValfsTer4	frameshift_variant	Exon 7 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1043delG	p.Gly348ValfsTer4	frameshift_variant	Exon 8 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*839delG		non_coding_transcript_exon_variant	Exon 12 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*839delG		3_prime_UTR_variant	Exon 12 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 4 AN: 166844 Hom.: 0 AF XY: 0.0000114 AC XY: 1 AN XY: 88098

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: 0.0000599

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000853 AC: 12 AN: 1406150 Hom.: 0 Cov.: 31 AF XY: 0.0000130 AC XY: 9 AN XY: 694190

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: 0.0000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Nov 30, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 14, 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.Gly348Valfs*4) 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 (rs781013226, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive limb girdle muscular dystrophy (PMID: 15733273, 25135358). ClinVar contains an entry for this variant (Variation ID: 286813). For these reasons, this variant has been classified as Pathogenic. -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Gly348ValfsTer4 variant in CAPN3 was identified by our study in one individual in the compound heterozygous state, with a likely pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD) The presence of this variant in combination with a likely pathogenic variant and in an individual with LGMD increases the likelihood that the p.Gly348ValfsTer4 variant is pathogenic. This variant has been identified in 0.002838% (3/105690) of European (non-Finnish) chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781013226). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 348 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive LGMD. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and the presence of another likely pathogenic variant in an individual with Limb-Girdle Muscular Dystrophy. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015). -

not provided Pathogenic:2

Mar 17, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs781013226; hg19: chr15-42686465;