rs376107921

Variant names:

• chr15-42399617-G-A
• rs376107921
• NM_000070.3:c.1319G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-42399617-G-A
• chr15-42399617-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP4_Strong PP3 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1319G>A variant in CAPN3 is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid 440 (p.Arg440Gln). This variant has been detected in at least 12 individuals with a clinical diagnosis or suspicion of limb girdle muscular dystrophy (PMID:20694146, 18055493, 17994539, 18334579, 18854869, 15689361, 19048948, 21984748; Washington University internal clinic data communication), including confirmed in trans with a pathogenic variant (c.550del, 1.0 pt, PMID:17994539), and in unknown phase with a likely pathogenic or pathogenic variant in three cases (c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 0.5 pts, PMID:21984748; c.633G>C p.(Lys211Asn), 0.5 pts, PMID:18334579, 20694146, 18055493) (PM3_Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed absent calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID:18055493, 20694146, 18854869, 19048948). The filtering allele frequency of the variant is 0.0004336 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 7/30318), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.79, 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 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_Strong, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA347525/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 6.90
• 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):

• 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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.1319G>A	p.Arg440Gln	missense	Exon 10 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.1319G>A	p.Arg440Gln	missense	Exon 10 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.1175G>A	p.Arg392Gln	missense	Exon 9 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.1319G>A	p.Arg440Gln	missense	Exon 10 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.1319G>A	p.Arg440Gln	missense	Exon 10 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.1175G>A	p.Arg392Gln	missense	Exon 9 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000646 AC: 16 AN: 247616 AF XY: 0.000105

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.0000626

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000147 AC: 214 AN: 1458920 Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 111 AN XY: 725320

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.0000225 AC: 1 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.000256 AC: 22 AN: 86046

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5272

European-Non Finnish (NFE) AF: 0.000162 AC: 180 AN: 1110388

Other (OTH) AF: 0.000149 AC: 9 AN: 60216

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152196 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74342

African (AFR) AF: 0.000145 AC: 6 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (4)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (2)
1	-	-	Abnormality of the musculature (1)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.96
MPC		0.67
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.57
gMVP		0.80
Mutation Taster		=13/87	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: rs376107921; hg19: chr15-42691815; COSMIC: COSV58821007; COSMIC: COSV58821007;