rs1274808359

Positions:

• chr15-42401667-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_000070.3(CAPN3):​c.1381C>T​(p.Arg461Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 6.06

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 14 ACMG points.

• PM1: In a region_of_interest Domain III (size 168) in uniprot entity CAN3_HUMAN there are 132 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 15-42401667-C-T is Pathogenic according to our data. Variant chr15-42401667-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 501440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42401667-C-T is described in Lovd as [Pathogenic]. Variant chr15-42401667-C-T is described in Lovd as [Pathogenic]. Variant chr15-42401667-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1381C>T	p.Arg461Cys	missense_variant	11/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1381C>T	p.Arg461Cys	missense_variant	11/23		NP_077320.1
CAPN3	NM_173087.2	c.1237C>T	p.Arg413Cys	missense_variant	10/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1381C>T	p.Arg461Cys	missense_variant	11/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*1177C>T		non_coding_transcript_exon_variant	15/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*1177C>T		3_prime_UTR_variant	15/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152150 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: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251432 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74312

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: 0.000189

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 461 of the CAPN3 protein (p.Arg461Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10567047, 11525884, 18337726). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 501440). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN3 protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 15, 2018	The homozygous p.Arg461Cys variant was identified by our study in one individual with limb-girdle musculardDystrophy. This variant has been identified in the literature in four homozygous probands and one proband that was compound heterozygous for the p.Arg461Cys variant as well as the c.801+1G>A variant (Minami et al. 1999, PMID: 10567047; Chae et al. 2001, PMID: 11525884). This variant has been identified in <0.01% (1/17240) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). The Arginine (Arg) at position 461 is highly conserved in mammals and evolutionarily distant species, supporting that a change at this position may not be tolerated. Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is also located in a mutational hotspot in a gene that does not have many benign missense mutations. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 03, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 09, 2017	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 23, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CAPN3: PM3:Strong, PM2, PP3 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 29, 2024

- -

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

May 18, 2023

Variant summary: CAPN3 c.1381C>T (p.Arg461Cys) results in a non-conservative amino acid change located in the Peptidase C2, large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251432 control chromosomes (gnomAD). c.1381C>T has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Chae_2011 and Duno_2008). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11525884, 18337726). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely 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

Apr 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;.;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.1	.;M;.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.2	.;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.92
MutPred		0.81		.;Loss of disorder (P = 0.0676);.;Loss of disorder (P = 0.0676);
MVP		0.97
MPC		0.73
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.71
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1274808359; hg19: chr15-42693865; COSMIC: COSV58820033; COSMIC: COSV58820033;