rs794726871

Positions:

• chr15-42359950-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5 PP3_Moderate PP5_Very_Strong

The NM_000070.3(CAPN3):​c.145C>T​(p.Arg49Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,014 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.05

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 12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42359951-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 15-42359950-C-T is Pathogenic according to our data. Variant chr15-42359950-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 193037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42359950-C-T is described in Lovd as [Pathogenic]. Variant chr15-42359950-C-T is described in Lovd as [Pathogenic]. Variant chr15-42359950-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.145C>T	p.Arg49Cys	missense_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.145C>T	p.Arg49Cys	missense_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.145C>T	p.Arg49Cys	missense_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.145C>T	p.Arg49Cys	missense_variant	1/24	1	NM_000070.3	ENSP00000380349	P2
CAPN3	ENST00000357568.8	c.145C>T	p.Arg49Cys	missense_variant	1/23	1		ENSP00000350181
CAPN3	ENST00000349748.8	c.145C>T	p.Arg49Cys	missense_variant	1/21	1		ENSP00000183936
CAPN3	ENST00000318023.11	c.145C>T	p.Arg49Cys	missense_variant	1/23	5		ENSP00000326281	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 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: 0.0000239 AC: 6 AN: 251372 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135850

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: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

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

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 14, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 27, 2018	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Occurs in three or more cases with a recessive pathogenic variant in the same gene. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2016	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 49 of the CAPN3 protein (p.Arg49Cys). This variant is present in population databases (rs794726871, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 18055493, 18334579, 19285864, 19556129, 28403181). 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: 193037). 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) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg49 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16650086, 17318636, 25135358). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	Dec 03, 2018	The heterozygous p.Arg49Cys variant in CAPN3 was identified by our study in the compound heterozygous state, with reported VUS variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.002437% (6/246158) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794726871). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg49Cys variant in CAPN3 has been reported in 2 individuals with LGMD (PMID: 18334579, 19285864). Also, the presence of this variant in combination with a reported pathogenic variant and in an individual with LGMD increases the likelihood that the p.Arg49Cys variant is pathogenic (Variation ID: 166790). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This missense variant affects the same residue as the likely pathogenic p.Arg49His variant, raising the possibility that a change at this residue may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg49Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PM5, PP3 (Richards 2015). -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 10, 2017	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 06, 2023

Variant summary: CAPN3 c.145C>T (p.Arg49Cys) results in a non-conservative amino acid change in 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 2.4e-05 in 251372 control chromosomes. c.145C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Groen_2007, Charlton_2009, Meinke_2020, Alharbi_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	0.90	.;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.80
MutPred		0.80		Loss of solvent accessibility (P = 0.0079);Loss of solvent accessibility (P = 0.0079);Loss of solvent accessibility (P = 0.0079);Loss of solvent accessibility (P = 0.0079);
MVP		0.95
MPC		0.74
ClinPred		0.71	D
GERP RS		5.0
Varity_R		0.17
gMVP		0.86

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: rs794726871; hg19: chr15-42652148; COSMIC: COSV58824966; COSMIC: COSV58824966;