chr15-42410460-G-T

Variant names:

• chr15-42410460-G-T
• rs770894443
• NM_000070.3:c.2148G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4_Strong PP3 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.2148G>T variant in CAPN3 is a missense variant predicted to cause the substitution of glutamic acid to aspartic acid at codon 716, p.(Glu716Asp). This variant has been reported in at least five individuals with features consistent with LGMD (PMID:15689361, 32994280, 37526466; LOVD CAPN3_000296), including in a homozygous state in one patient without reported familial consanguinity (0.5 pts; PMID:15689361, LOVD Individual #00311346), confirmed in trans with a likely pathogenic or pathogenic variant (c.1401_1403del p.(Glu467del), 1.0 pt, PMID:37526466), and in unknown phase with a pathogenic variant (c.967G>T p.(Glu323Ter), 0.5 pts, PMID:15689361) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in CAPN3 had both a clinical diagnosis of LGMD and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID:15689361; PP4_Strong). The filtering allele frequency for this variant is 0.000008232 (the upper threshold of the 95% CI of 4/11112002 European (non-Finnish) exome chromosomes in gnomAD v4.1.0), which is less than the LGMD VCEP threshold (0.0001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.84, evidence which 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; 06/25/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10605085/MONDO:0015152/187

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8 U:1
• Conservation: PhyloP100: 0.726
• Publications: 1 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 10 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.2148G>T	p.Glu716Asp	missense	Exon 20 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.2130G>T	p.Glu710Asp	missense	Exon 19 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.1872G>T	p.Glu624Asp	missense	Exon 17 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.2148G>T	p.Glu716Asp	missense	Exon 20 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.2130G>T	p.Glu710Asp	missense	Exon 19 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.1872G>T	p.Glu624Asp	missense	Exon 17 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 86258

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: 0.00000360 AC: 4 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.73
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.94		Gain of MoRF binding (P = 0.1041)
MVP		0.94
MPC		0.25
ClinPred		0.98	D
GERP RS		2.7
Varity_R		0.78
gMVP		0.83
Mutation Taster		=6/94	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: rs770894443; hg19: chr15-42702658;