rs139836397

Positions:

chr15-42399555-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_SupportingPM3_StrongPP3PP4

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1257T>G variant in CAPN3 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 419 (p.Asp419Glu). This variant has been detected in at least ten unrelated individuals with LGMD (PMID:18055493, 25079074, 30564623; LOVD CAPN3_000280; ClinVar SCV000953543.3 internal data communication, ClinVar SCV002025057.3 internal data communication, ClinVar SCV001879783.1 internal data communication), including in unknown phase with a pathogenic variant in six cases (c.550delA p.(Thr184ArgfsTer36), 1.0 pt, PMID:18055493, SCV002025057.3; c.1469G>A p.(Arg490Gln), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1027G>T p.(Glu343Ter), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1838del p.(Lys613ArgfsTer49), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.643_663del p.(Ser215_Gly221del), 0.5 pts, ClinVar SCV001879783.1 internal data communication) (PM3_Strong). In four individuals, a second variant in CAPN3 was not identified. At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PMID:18055493) (PP4). The filtering allele frequency of this variant is 0.00006819 (the upper threshold of the 95% CI of 3/113704 European (non-Finnish) exome alleles) by gnomAD v2.1.1, which is less than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.83, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4, PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511304/MONDO:0015152/187

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:2

Conservation

PhyloP100: -0.201

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3 linkuse as main transcript	c.1257T>G	p.Asp419Glu	missense_variant	10/24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 linkuse as main transcript	c.1257T>G	p.Asp419Glu	missense_variant	10/23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 linkuse as main transcript	c.1113T>G	p.Asp371Glu	missense_variant	9/21		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.1257T>G	p.Asp419Glu	missense_variant	10/24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 linkuse as main transcript	n.*1053T>G		non_coding_transcript_exon_variant	14/26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 linkuse as main transcript	n.*1053T>G		3_prime_UTR_variant	14/26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

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:

0.0000199

AC:

AN:

251390

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460192

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726514

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74304

show subpopulations

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:

0.0000497

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 13, 2019	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 07, 2024

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 09, 2025

The NM_000070.3: c.1257T>G variant in CAPN3 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 419 (p.Asp419Glu). This variant has been detected in at least ten unrelated individuals with LGMD (PMID: 18055493, 25079074, 30564623; LOVD CAPN3_000280; ClinVar SCV000953543.3 internal data communication, ClinVar SCV002025057.3 internal data communication, ClinVar SCV001879783.1 internal data communication), including in unknown phase with a pathogenic variant in six cases (c.550delA p.(Thr184ArgfsTer36), 1.0 pt, PMID: 18055493, SCV002025057.3; c.1469G>A p.(Arg490Gln), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1027G>T p.(Glu343Ter), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1838del p.(Lys613ArgfsTer49), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.643_663del p.(Ser215_Gly221del), 0.5 pts, ClinVar SCV001879783.1 internal data communication) (PM3_Strong). In four individuals, a second variant in CAPN3 was not identified. At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PMID: 18055493) (PP4). The filtering allele frequency of this variant is 0.00006819 (the upper threshold of the 95% CI of 3/113704 European (non-Finnish) exome alleles) by gnomAD v2.1.1, which is less than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.83, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4, PM2_Supporting, PP3. -

CAPN3-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The CAPN3 c.1257T>G variant is predicted to result in the amino acid substitution p.Asp419Glu. This variant was reported along with a second early termination change (phase not specified) in two brothers with limb-girdle muscular dystrophy (LGMD), and functional studies support its pathogenicity (Groen et al. 2007. PubMed ID: 18055493; Garnham et al. 2009. PubMed ID: 19226146). It has also been reported in the heterozygous state in one carrier and one affected individual in whom no second CAPN3 variant was detected (Capalbo et al. 2019. PubMed ID: 31589614; Nilsson et al. 2014. PubMed ID: 25079074). A different amino acid change at same position (p.Asp419Gly) has also been reported along with a second CAPN3 variant in patient with LGMD (Groen et al. 2007. PubMed ID: 18055493). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 419 of the CAPN3 protein (p.Asp419Glu). This variant is present in population databases (rs139836397, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 18055493, 25079074). ClinVar contains an entry for this variant (Variation ID: 282873). 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 not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.090

T;.;.;D

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.1

.;M;.;M

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.030

D;D;T;D

Polyphen

1.0, 0.94, 0.98

.;D;P;D

Vest4

0.94

MutPred

0.83

.;Gain of solvent accessibility (P = 0.0638);.;Gain of solvent accessibility (P = 0.0638);

MVP

0.90

MPC

0.53

ClinPred

0.93

GERP RS

-5.1

Varity_R

0.93

gMVP

0.77

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

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