15-42410645-C-T

Variant names:

• chr15-42410645-C-T
• rs768090444
• NM_000070.3:c.2242C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PP4_Moderate PM3

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.2242C>T p.(Arg748Ter) variant in CAPN3, which is also known as p.(Arg748del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 21/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. mRNA analysis demonstrated reduced expression of the transcript containing the variant, consistent with nonsense mediated decay (PMID:17157502) (PVS1). This variant has been detected in at least six individuals reported to have autosomal recessive LGMD (PMID:25214167, 12461690, 16971480, 17157502, 18055493; Washington University internal clinic data communication). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID:16971480), and in at least two cases, the variant was identified in trans with a second CAPN3 variant not yet curated by the VCEP and considered VUS (0.5 pts, PMID:12461690, 17157502) (PM3). 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:16971480). The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), which is more than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). 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_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511779/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CAPN3 NM_000070.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 4.21

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.
• 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.2242C>T	p.Arg748*	stop_gained	Exon 21 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2242C>T	p.Arg748*	stop_gained	Exon 21 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.247C>T	p.Arg83*	stop_gained	Exon 8 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.247C>T	p.Arg83*	stop_gained	Exon 8 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.247C>T	p.Arg83*	stop_gained	Exon 9 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.247C>T	p.Arg83*	stop_gained	Exon 8 of 11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.145C>T	p.Arg49*	stop_gained	Exon 8 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2678C>T		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2678C>T		3_prime_UTR_variant	Exon 23 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151884 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251104 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135722

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461646 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151884 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74168

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000297 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:5

Mar 24, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3,PP4. -

Dec 06, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 20, 2025

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.Arg748*) 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 (rs768090444, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 12461690, 16971480, 17157502, 18055493). ClinVar contains an entry for this variant (Variation ID: 283259). For these reasons, this variant has been classified as Pathogenic. -

Dec 27, 2023

3billion

Significance: 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: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000283259 /PMID: 12461690). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

May 16, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with LGMD, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Dec 16, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Jun 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

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.2242C>T p.(Arg748Ter) variant in CAPN3, which is also known as p.(Arg748del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 21/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. mRNA analysis demonstrated reduced expression of the transcript containing the variant, consistent with nonsense mediated decay (PMID: 17157502) (PVS1). This variant has been detected in at least six individuals reported to have autosomal recessive LGMD (PMID: 25214167, 12461690, 16971480, 17157502, 18055493; Washington University internal clinic data communication). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 16971480), and in at least two cases, the variant was identified in trans with a second CAPN3 variant not yet curated by the VCEP and considered VUS (0.5 pts, PMID: 12461690, 17157502) (PM3). 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: 16971480). The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), which is more than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). 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_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.90
GERP RS		3.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs768090444; hg19: chr15-42702843;