rs886043432

Variant names:

• chr15-42401810-G-A
• rs886043432
• NM_000070.3:c.1524G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PM3_Strong PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1524G>A variant in CAPN3 is a synonymous (silent) variant (p.Glu508=) that affects the last nucleotide of exon 11. This variant has been detected in at least seven individuals with LGMD (PMID:26404900, 17236769, 17994539, 16141003, 32528171; ClinVar SCV001423802.2 internal data communication). Of those individuals, at least three were compound heterozygous, and in at least two, the variant was confirmed in trans with a pathogenic variant (c.550del p.(Thr184ArgfsTer36), 2.0 pts, PMID:17236769, 17994539). In addition, at least one individual was homozygous for the variant (0.5 pts, PMID:17994539) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3 protein, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID:17236769). This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting). The SpliceAI prediction score for this variant is 0.66 (donor loss), which is greater than the VCEP threshold of ≥ 0.50 and suggestive of an impact on splicing (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; 01/07/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10605515/MONDO:0015152/187

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 9.92

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1524G>A	p.Glu508Glu	splice_region_variant, synonymous_variant	Exon 11 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1524G>A	p.Glu508Glu	splice_region_variant, synonymous_variant	Exon 11 of 23		NP_077320.1
CAPN3	NM_173087.2	c.1380G>A	p.Glu460Glu	splice_region_variant, synonymous_variant	Exon 10 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1524G>A	p.Glu508Glu	splice_region_variant, synonymous_variant	Exon 11 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*1320G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 15 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*1320G>A		3_prime_UTR_variant	Exon 15 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:2

Nov 14, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PP3,PP4. -

Apr 18, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1 Uncertain:1

Mar 24, 2020

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CAPN3 c.1524G>A (p.Glu508Glu) is a synonymous splice region variant. The p.Glu508Glu variant has been reported in two studies in which it was identified in at least two individuals affected with limb girdle muscular dystrophy, in one in a homozygous state and in the other in a compound heterozygous state. In both patients, immunohistochemistry of tissue from muscle biopsy showed either neglible or absent Calpain-3 protein levels compared to normal controls (Guglieri et al. 2008). In addition, Milic et al. (2007), demonstrated that protein extracted from the muscle biopsy of a patient who carriend the p.Glu508Glu variant in a compound heterozygous state, did not have any Calpain-3 protein activity. The p.Glu508Glu variant is not found in the Genome Aggregation Database, in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of ACMG criteria, the p.Glu508Glu variant is classified as likely pathogenic for calpainopathy. -

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 508 of the CAPN3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CAPN3 protein. This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with limb-girdle muscle weakness and/or limb-girdle muscular dystrophy (PMID: 16141003, 17994539, 32528171). ClinVar contains an entry for this variant (Variation ID: 286592). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Jun 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 07, 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.1524G>A variant in CAPN3 is a synonymous (silent) variant (p.Glu508=) that affects the last nucleotide of exon 11. This variant has been detected in at least seven individuals with LGMD (PMID: 26404900, 17236769, 17994539, 16141003, 32528171; ClinVar SCV001423802.2 internal data communication). Of those individuals, at least three were compound heterozygous, and in at least two, the variant was confirmed in trans with a pathogenic variant (c.550del p.(Thr184ArgfsTer36), 2.0 pts, PMID: 17236769, 17994539). In addition, at least one individual was homozygous for the variant (0.5 pts, PMID: 17994539) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3 protein, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 17236769). This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting). The SpliceAI prediction score for this variant is 0.66 (donor loss), which is greater than the VCEP threshold of ≥ 0.50 and suggestive of an impact on splicing (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; 01/07/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. -

not provided Pathogenic:1

May 25, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs886043432; hg19: chr15-42694008;