rs398123146

Positions:

• chr15-42360025-C-CT

Variant summary

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

The NM_000070.3(CAPN3):​c.223dupT​(p.Tyr75fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000274 in 1,461,864 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: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 5.08

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 15-42360025-C-CT is Pathogenic according to our data. Variant chr15-42360025-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 92411.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.223dupT	p.Tyr75fs	frameshift_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.223dupT	p.Tyr75fs	frameshift_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.223dupT	p.Tyr75fs	frameshift_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.223dupT	p.Tyr75fs	frameshift_variant	1/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*105+5575dupT		intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727234

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: 0.0000351

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2022	This sequence change creates a premature translational stop signal (p.Tyr75Leufs*5) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 92411). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2023	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: 27854218, 15689361, 10330340, 19556129, 31589614, Schiava2022[casereport], 31931849, 30564623) -

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

Pathogenic, flagged submission

clinical testing

Baylor Genetics

Jul 21, 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

Oct 08, 2024

Variant summary: CAPN3 c.223dupT (p.Tyr75LeufsX5) 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 249924 control chromosomes (gnomAD). c.223dupT has been reported in the literature in at least an individual affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Punetha_2016). The following publication have been ascertained in the context of this evaluation (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 92411). Based on the evidence outlined above, the variant was classified as pathogenic. -

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: rs398123146; hg19: chr15-42652223;