rs149095128

Variant names:

• chr15-42411299-C-A
• rs149095128
• NM_000070.3:c.2393C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000070.3(CAPN3):​c.2393C>A​(p.Ala798Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A798T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.91
• Publications: 11 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 8 ACMG points.

• PP5: Variant 15-42411299-C-A is Pathogenic according to our data. Variant chr15-42411299-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 92414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2393C>A	p.Ala798Glu	missense_variant	Exon 23 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2393C>A	p.Ala798Glu	missense_variant	Exon 23 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.398C>A	p.Ala133Glu	missense_variant	Exon 10 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.398C>A	p.Ala133Glu	missense_variant	Exon 10 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.398C>A	p.Ala133Glu	missense_variant	Exon 11 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.398C>A	p.Ala133Glu	missense_variant	Exon 10 of 11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.296C>A	p.Ala99Glu	missense_variant	Exon 10 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2829C>A		non_coding_transcript_exon_variant	Exon 25 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2829C>A		3_prime_UTR_variant	Exon 25 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

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: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000795 AC: 20 AN: 251420 AF XY: 0.0000589

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000198 AC: 290 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.000197 AC XY: 143 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000257 AC: 286 AN: 1111938

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 9 AN XY: 74366

African (AFR) AF: 0.0000483 AC: 2 AN: 41442

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:7

Oct 27, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 798 of the CAPN3 protein (p.Ala798Glu). This variant is present in population databases (rs149095128, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy type 2A (PMID: 17994539, 18055493, 18337726, 19556129, 22443334, 23169433, 25135358; internal data). 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: 92414). 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: 11053681, 17994539, 18055493, 18337726, 19556129, 22443334). For these reasons, this variant has been classified as Pathogenic. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across eight studies, the CAPN3 c.2393C>A (p.Ala798Glu) missense variant was identified in 11 patients with calpainopathy, including two homozygotes, eight compound heterozygotes, and one heterozygote in whom a second variant was not identified (Anderson et al. 2000; Groen et al. 2007; Duno et al. 2008; Charlton R et al. 2009; Hauerslev et al. 2012; Sveen et al. 2013; Stehlíková et al. 2014; Kuhn et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ala798Glu variant is classified as pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 26, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace alanine with glutamic acid at codon 798 of the CAPN3 protein, p.(Ala798Glu). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the Penta E-F hand (PEF) domain (PMID: 26363099). There is a large physicochemical difference between alanine and glutamic acid. The variant is present in a large population cohort at a frequency of 0.01%, which is consistent with a recessive condition (rs149095128, 28/282,814 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified homozygous and with a second pathogenic allele in multiple individuals with limb-girdle muscular dystrophy and segregates with the condition in at least one family (PMID: 18055493, 19556129, 22443334, 25135358, 26886200; LOVD). Absent or reduced calpain 3 protein expression has been identified in the muscle biopsies of multiple cases with the variant (PMID: 18055493, 18337726, 19556129). Multiple lines of computational evidence have conflicting predictions for the missense substitution (2/4 algorithms predict deleterious). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PP1, PP4. -

not provided Pathogenic:3

Feb 08, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2025

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: 10330340, 25525159, 11053681, 25135358, 27447704, 22443334, 18055493, 17994539, 18337726, 19556129, 26886200, 34405919, 37273706, 30919934) -

Mar 30, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 26, 2024

Baylor Genetics

Significance: Likely 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 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Dec 28, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CAPN3 c.2393C>A (p.Ala798Glu) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251420 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (8e-05 vs 0.0032), allowing no conclusion about variant significance. c.2393C>A has been reported in the literature in multiple individuals affected with limb girdle muscular dystrophy type 2A (Groen_2007, Guglieri_2008, Duno_2008, Charlton_2009, Hauerslev_2012), including at least one homozygote. These data indicate that the variant is very likely to be associated with disease. Western blot results showed reduced or absent Calpain-3 protein at 94kDa and 30kDa from patients samples who carried this variant (Groen_2007, Guglieri_2008, Duno_2008, Charlton_2009, Hauerslev_2012). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=7) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T;.;.;T;.;.;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D;T;D;D;D;.;T;.;D;.
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.6	.;.;.;L;.;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	.;N;N;N;D;D;D;.;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.15	.;T;T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.98	T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.98	.;D;D;D;.;.;.;.;.;.;.
Vest4		0.88
MVP		0.99
MPC		0.68
ClinPred		0.83	D
GERP RS		6.2
Varity_R		0.49
gMVP		0.81
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs149095128; hg19: chr15-42703497;