rs886042557

Variant names:

• chr15-42409985-C-T
• rs886042557
• NM_000070.3:c.2105C>T

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PP4_Strong PP3 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.2105C>T variant in CAPN3 is a missense variant expected to result in the substitution of alanine with valine at amino acid 702, p.(Ala702Val). This variant has been detected in at least 11 individuals with features consistent with LGMD (PMID:19556129; 31937337; 35741838; 16141003; 27066573; 16650086; ClinVar SCV001218172.5 internal data communication). Five seemingly unrelated patients were homozygous, with familial consanguinity reported in four (0.25 pts x4, 0.5 pts x1, capped at 1.0 pt). Two patients had a likely pathogenic or pathogenic CAPN3 variant confirmed in trans (c.1993-1G>A, 1.0 pt, ClinVar SCV001218172.5 internal data communication; c.1981del p.(Gln660_Ile661insTer), 1.0 pt, PMID:19556129), and two patients had a pathogenic variant in unknown phase (c.2120A>G (p.Asp707Gly), 0.5 pts, PMID:27066573; c.2362_2363delinsTCATCT (p.Arg788SerfsTer14), 0.5 pts, PMID:35741838) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID:19556129) (PP4_Strong). The filtering allele frequency of this variant is 0.000011828 in gnomAD v4.1.0 exomes (the upper bound of the 95% confidence interval of 7/1111640 European (non-Finnish) chromosomes), which is lower than the LGMD VCEP threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.77, which is above the LGMD 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 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; 05/14/2025): PM3_Very Strong, PP4_Strong, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10604398/MONDO:0015152/187

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 4.05
• Publications: 5 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: Pathogenic. The variant received 8 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 rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2105C>T	p.Ala702Val	missense_variant	Exon 19 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2105C>T	p.Ala702Val	missense_variant	Exon 19 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.110C>T	p.Ala37Val	missense_variant	Exon 6 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.110C>T	p.Ala37Val	missense_variant	Exon 6 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.110C>T	p.Ala37Val	missense_variant	Exon 7 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.110C>T	p.Ala37Val	missense_variant	Exon 6 of 11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.8C>T	p.Ala3Val	missense_variant	Exon 6 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2541C>T		non_coding_transcript_exon_variant	Exon 21 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2541C>T		3_prime_UTR_variant	Exon 21 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251260 AF XY: 0.0000147

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: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459604 Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6 AN XY: 726132

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53404

Middle Eastern (MID) AF: 0.000236 AC: 1 AN: 4232

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111640

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:4

Sep 27, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000283099 /PMID: 9150160). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 17236769, 27262448). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 13, 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. -

Mar 12, 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 valine, which is neutral and non-polar, at codon 702 of the CAPN3 protein (p.Ala702Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 16141003, 17236769, 27234031, 27262448, 30056071). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 283099). 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%. For these reasons, this variant has been classified as Pathogenic. -

Jun 08, 2024

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM5,PP5,PM2,PP3,PP2,PM1? -

not provided Pathogenic:2

Sep 15, 2015

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a 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: 30056071, 27234031, 10330340, 9150160, 19556129, 16411092, 16650086, 15757244, 9266733, 27262448, 17994539, 17236769, 16141003, 35741838) -

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

Feb 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

May 14, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000070.3: c.2105C>T variant in CAPN3 is a missense variant expected to result in the substitution of alanine with valine at amino acid 702, p.(Ala702Val). This variant has been detected in at least 11 individuals with features consistent with LGMD (PMID: 19556129; 31937337; 35741838; 16141003; 27066573; 16650086; ClinVar SCV001218172.5 internal data communication). Five seemingly unrelated patients were homozygous, with familial consanguinity reported in four (0.25 pts x4, 0.5 pts x1, capped at 1.0 pt). Two patients had a likely pathogenic or pathogenic CAPN3 variant confirmed in trans (c.1993-1G>A, 1.0 pt, ClinVar SCV001218172.5 internal data communication; c.1981del p.(Gln660_Ile661insTer), 1.0 pt, PMID: 19556129), and two patients had a pathogenic variant in unknown phase (c.2120A>G (p.Asp707Gly), 0.5 pts, PMID: 27066573; c.2362_2363delinsTCATCT (p.Arg788SerfsTer14), 0.5 pts, PMID: 35741838) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 19556129) (PP4_Strong). The filtering allele frequency of this variant is 0.000011828 in gnomAD v4.1.0 exomes (the upper bound of the 95% confidence interval of 7/1111640 European (non-Finnish) chromosomes), which is lower than the LGMD VCEP threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.77, which is above the LGMD 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 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; 05/14/2025): PM3_Very Strong, PP4_Strong, PP3, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;.;D;.;D;.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.5	.;.;.;M;.;.;.;.;.;.;.;.
PhyloP100		4.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	.;N;N;N;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	.;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;.;.;.;.;.;.
Vest4		0.95
MutPred		0.85		.;.;.;Loss of disorder (P = 0.1191);.;.;.;.;.;.;.;.;
MVP		0.96
MPC		0.63
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.70
gMVP		0.66
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs886042557; hg19: chr15-42702183;