rs766334893

Variant names:

• chr15-42392720-G-T
• rs766334893
• NM_000070.3:c.1027G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PP4 PM2_Supporting PM3

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1027G>T (p.Glu343Ter) variant in CAPN3, which is also known as p.(Glu343del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least five individuals with features of limb girdle muscular dystrophy (PMID:34628793, 30564623; LOVD CAPN3_000602; ClinVar SCV000953543.3 internal data communication), including in unknown phase with a pathogenic variant in two cases (c.1468C>T p.(Arg490Trp), 1.0 pt, PMID:30564623; LOVD Individual #00222348; ClinVar SCV000953543.3 internal data communication) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy (PP4). The highest population minor allele frequency of the variant is 0.00005787 (2/34560 exome chromosomes) in the Admixed American population of gnomAD v2.1.1, which is less than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). 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): PVS1, PM3, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511222/MONDO:0015152/187

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAPN3 NM_000070.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9887
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 6.67

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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.1027G>T	p.Glu343*	stop_gained, splice_region_variant	Exon 7 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1027G>T	p.Glu343*	stop_gained, splice_region_variant	Exon 7 of 23		NP_077320.1
CAPN3	NM_173087.2	c.883G>T	p.Glu295*	stop_gained, splice_region_variant	Exon 6 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1027G>T	p.Glu343*	stop_gained, splice_region_variant	Exon 7 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*823G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*823G>T		3_prime_UTR_variant	Exon 11 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250884 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135652

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461222 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

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

Aug 11, 2024

Medical Molecular Genetics Department, National Research Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

By applying ACMG guidelines: According to insilico studies, the variant is classified as deleterious (PP3),our study patient’s clinical phenotype is typically correlated to the disease (PP4), it showed an extremely low frequency in gnomAD population databases (PS4). Null variant in a gene where loss of function is a known mechanism of disease (PVS1). so according to ACMG guidlines it is classified as variant of uncertain significance. -

Apr 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu343*) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is present in population databases (rs766334893, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 497182). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Apr 12, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E343X variant in the CAPN3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E343X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret E343X as a pathogenic variant. -

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

Jul 10, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 09, 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.1027G>T (p.Glu343Ter) variant in CAPN3, which is also known as p.(Glu343del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least five individuals with features of limb girdle muscular dystrophy (PMID: 34628793, 30564623; LOVD CAPN3_000602; ClinVar SCV000953543.3 internal data communication), including in unknown phase with a pathogenic variant in two cases (c.1468C>T p.(Arg490Trp), 1.0 pt, PMID: 30564623; LOVD Individual #00222348; ClinVar SCV000953543.3 internal data communication) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy (PP4). The highest population minor allele frequency of the variant is 0.00005787 (2/34560 exome chromosomes) in the Admixed American population of gnomAD v2.1.1, which is less than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). 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): PVS1, PM3, PP4, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	57
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
Vest4		0.85
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs766334893; hg19: chr15-42684918;