rs141656719

Variant names:

• chr15-42401754-C-T
• rs141656719
• NM_000070.3:c.1468C>T
• CAPN3 p.Arg490Trp

Your query was ambiguous. Multiple possible variants found:

• chr15-42401754-C-T
• chr15-42401754-C-A
• chr15-42401754-C-G

Variant summary

Our verdict is Pathogenic. The variant received 5 ACMG points: 5P and 0B. PP4_Moderate PP3 PM3

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1468C>T variant in CAPN3 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 490 (p.Arg490Trp). This variant has been detected in at least 18 individuals with limb girdle muscular dystrophy (PMID:18055493, 10330340, 25214167, 25135358, 26632398, 12461690, 17994539), including in a homozygous state in at least two cases (1.0 pt; PMID:18055493), confirmed in trans with a pathogenic variant in one case (c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID:17994539), and in unknown phase with a pathogenic variant in four cases c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID:25135358; c.2279dup p.(Asn760LysfsTer5), 0.5 pts, PMID:18055493; c.2242C>T p.(Arg748Ter), 0.5 pts, PMID:25214167) (PM3_Very Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID:17994539). The highest population minor allele frequency of this variant is 0.0004598 (4/8700 genome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.84, which is above 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 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_Very Strong, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA233621/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:24 O:1
• Conservation: PhyloP100: -0.0230
• Publications: 32 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):

• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• 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, Labcorp Genetics (formerly Invitae), Myriad Women's Health
• limb-girdle muscular dystrophy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000258461 (HGNC:):

ACMG classification

Specifications for CAPN3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 5 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.1468C>T	p.Arg490Trp	missense	Exon 11 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.1468C>T	p.Arg490Trp	missense	Exon 11 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.1324C>T	p.Arg442Trp	missense	Exon 10 of 21	NP_775110.1	P20807-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1468C>T	p.Arg490Trp	missense	Exon 11 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.1468C>T	p.Arg490Trp	missense	Exon 11 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.1324C>T	p.Arg442Trp	missense	Exon 10 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000836 AC: 21 AN: 251162 AF XY: 0.0000737

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000237 AC: 347 AN: 1461786 Hom.: 0 Cov.: 32 AF XY: 0.000260 AC XY: 189 AN XY: 727200

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39686

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

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

European-Non Finnish (NFE) AF: 0.000292 AC: 325 AN: 1111958

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74408

African (AFR) AF: 0.000265 AC: 11 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000128

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (8)
8	-	-	not provided (8)
3	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (4)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy (2)
2	-	-	CAPN3-related disorder (2)
1	-	-	Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		-0.023
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.87
gMVP		0.83
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs141656719;

hg19: chr15-42693952;

COSMIC: COSV58826976;

COSMIC: COSV58826976;