rs139836397

Variant names:

• chr15-42399555-T-G
• rs139836397
• NM_000070.3:c.1257T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PP4 PM2_Supporting PM3_Strong

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
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:2
• Conservation: PhyloP100: -0.201
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.1257T>G	p.Asp419Glu	missense	Exon 10 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.1257T>G	p.Asp419Glu	missense	Exon 10 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.1113T>G	p.Asp371Glu	missense	Exon 9 of 21	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1257T>G	p.Asp419Glu	missense	Exon 10 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.1257T>G	p.Asp419Glu	missense	Exon 10 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.1113T>G	p.Asp371Glu	missense	Exon 9 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251390 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1460192 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 726514

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1110514

Other (OTH) AF: 0.0000166 AC: 1 AN: 60320

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000334 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

May 09, 2018

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 10, 2020

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 18, 2025

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1 Uncertain:1

Jan 23, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000070.2(CAPN3):c.1257T>G(D419E) is a missense variant classified as likely pathogenic in the context of calpainopathy. D419E has been observed in cases with relevant disease (PMID: 18055493, 29382405, 30564623). Relevant functional assessments of this variant are not available in the literature. D419E has been observed in referenced population frequency databases. In summary, NM_000070.2(CAPN3):c.1257T>G(D419E) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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) 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.

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

Mar 07, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 09, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Sep 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.20
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.83		Gain of solvent accessibility (P = 0.0638)
MVP		0.90
MPC		0.53
ClinPred		0.93	D
GERP RS		-5.1
Varity_R		0.93
gMVP		0.77
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs139836397; hg19: chr15-42691753;