rs778768583

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000070.3(CAPN3):c.2338G>C(p.Asp780His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,844 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 8.15

Variant links:

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]

CAPN3 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a helix (size 18) in uniprot entity CAN3_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_000070.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 15-42410958-G-C is Pathogenic according to our data. Variant chr15-42410958-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 195641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42410958-G-C is described in Lovd as [Pathogenic]. Variant chr15-42410958-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2338G>C	p.Asp780His	missense_variant	Exon 22 of 24	ENST00000397163.8	NP_000061.1	P20807-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.2338G>C	p.Asp780His	missense_variant	Exon 22 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.343G>C	p.Asp115His	missense_variant	Exon 9 of 11			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.343G>C	p.Asp115His	missense_variant	Exon 9 of 11			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.343G>C	p.Asp115His	missense_variant	Exon 10 of 12			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.343G>C	p.Asp115His	missense_variant	Exon 9 of 11			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.241G>C	p.Asp81His	missense_variant	Exon 9 of 11			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2774G>C		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*2774G>C		3_prime_UTR_variant	Exon 24 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251408

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135860

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727230

show subpopulations

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:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:6Other:1

Feb 08, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 08, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 780 of the CAPN3 protein (p.Asp780His). This variant is present in population databases (rs778768583, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 15733273, 23666804, 25079074, 27011640). It is commonly reported in individuals of Agarwal North Indian ancestry (PMID: 15733273, 23666804, 25079074, 27011640). ClinVar contains an entry for this variant (Variation ID: 195641). Invitae Evidence 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 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. -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.2338G>Cp.Asp780His in CAPN3 gene which is an Agarwal founder mutation has been reported previously in homozygous and compound heterozygous state in multiple individuals with Limb girdle muscular dystrophy Khadlikar et al., 2016, Nilsson MI, et al., 2014. Experimental studies have shown that this missense change results in reduced protein expression and autolytic activity in muscle biopsy samples Nilsson MI et al., 2014. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/Pathogenic multiple submissions. The variant is predicted to be damaging by SIFT. The amino acid Aspartic acid at position 780 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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.Asp780His variant in CAPN3 was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.0008124% (2/246172) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778768583). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The variant is located in the well-established functional domain EF-hand 4, a domain involved in protein homodimerization (PMID: 24846670). In vitro functional studies with muscle biopsies provide some evidence that the p.Asp780His variant may impact protein function by reducing translation and autolytic activity (PMID: 25079074). However, these types of assays may not accurately represent biological function. The p.Asp780His variant in CAPN3 has been reported in 7 Indian Agarwal individuals with LGMD and is a known founder mutation in the Indian Agarwal community (PMID: 23666804). The presence of this variant in combination with a pathogenic variant by our study as well as a splice site variant in 5 individuals with LGMD increases the likelihood that the p.Asp780His variant is pathogenic (PMID: 23666804). This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 195641). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on its location in a well-established functional domain and multiple occurrences with other CAPN3 variants. ACMG/AMP Criteria applied: PM2, PP3, PM1, PS3_Supporting, PM3_Strong (Richards 2015). -

Sep 18, 2018

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The observed variant c.2338G>C (p.Asp780His) has not been reported in 1000 Genomes and has a minor allele frequency of 0.002% in the ExAC databases. The In silico prediction of the given variant is probably damaging by PolyPhen-2 and damaging by MutationTaster2 and SIFT. The above variant was observed as compound heterozygous along with the variant g.50431G>T (3'splice site). The variant g.50431G>T (3'splice site) has not been reported in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is damaging by MutationTaster2. -

not provided

Pathogenic:4

Sep 06, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21386772, 15733273, 23666804, 25079074, 27011640, 33337384, 33250842, 31069529, 35169782, 35723113) -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Mar 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.;.;D;.;.;.;.;.;.;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;.;D;.;D;.

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

.;.;.;M;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.1

.;D;D;D;D;D;D;.;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;D;D;D;D;D;.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;D;D;.;.;.;.;.;.;.

Vest4

0.96

MutPred

0.90

.;.;.;Loss of stability (P = 0.1125);.;.;.;.;.;.;.;

MVP

0.98

MPC

0.68

ClinPred

0.99

GERP RS

5.4

Varity_R

0.93

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over