15-42359806-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000070.3(CAPN3):c.2del(p.Met1?) variant causes a frameshift, start lost change. The variant allele was found at a frequency of 0.00000137 in 1,461,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAPN3 NM_000070.3 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.12

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 802 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_000070.3 (CAPN3) was described as [Pathogenic] in ClinVar as 2032843
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-42359806-AT-A is Pathogenic according to our data. Variant chr15-42359806-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 569125.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.2del	p.Met1?	frameshift_variant, start_lost	1/24	ENST00000397163.8
CAPN3	NM_024344.2	c.2del	p.Met1?	frameshift_variant, start_lost	1/23
CAPN3	NM_173087.2	c.2del	p.Met1?	frameshift_variant, start_lost	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.2del	p.Met1?	frameshift_variant, start_lost	1/24	1	NM_000070.3	P2
CAPN3	ENST00000357568.8	c.2del	p.Met1?	frameshift_variant, start_lost	1/23	1
CAPN3	ENST00000349748.8	c.2del	p.Met1?	frameshift_variant, start_lost	1/21	1
CAPN3	ENST00000318023.11	c.2del	p.Met1?	frameshift_variant, start_lost	1/23	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135712

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CAPN3 protein in which other variant(s) (p.Arg49Cys) have been determined to be pathogenic (PMID: 18055493, 18334579, 19285864, 19556129, 28403181). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 569125). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 25135358). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change affects the initiator methionine of the CAPN3 mRNA. The next in-frame methionine is located at codon 228. -

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: rs1566965806; hg19: chr15-42652004;