chr15-42388934-TGGTTCCTACGAAGCTCTGAAA-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM4PP3PP5_Very_Strong

The NM_000070.3(CAPN3):c.643_663delTCCTACGAAGCTCTGAAAGGT(p.Ser215_Gly221del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 9.90

Variant links:

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 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000070.3.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 15-42388934-TGGTTCCTACGAAGCTCTGAAA-T is Pathogenic according to our data. Variant chr15-42388934-TGGTTCCTACGAAGCTCTGAAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 217159.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-42388934-TGGTTCCTACGAAGCTCTGAAA-T is described in Lovd as [Pathogenic]. Variant chr15-42388934-TGGTTCCTACGAAGCTCTGAAA-T is described in Lovd as [Pathogenic]. Variant chr15-42388934-TGGTTCCTACGAAGCTCTGAAA-T is described in Lovd as [Pathogenic]. Variant chr15-42388934-TGGTTCCTACGAAGCTCTGAAA-T is described in Lovd as [Likely_pathogenic]. Variant chr15-42388934-TGGTTCCTACGAAGCTCTGAAA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.643_663delTCCTACGAAGCTCTGAAAGGT	p.Ser215_Gly221del	conservative_inframe_deletion	Exon 5 of 24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.643_663delTCCTACGAAGCTCTGAAAGGT	p.Ser215_Gly221del	conservative_inframe_deletion	Exon 5 of 23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.643_663delTCCTACGAAGCTCTGAAAGGT	p.Ser215_Gly221del	conservative_inframe_deletion	Exon 5 of 21		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.643_663delTCCTACGAAGCTCTGAAAGGT	p.Ser215_Gly221del	conservative_inframe_deletion	Exon 5 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 link	n.439_459delTCCTACGAAGCTCTGAAAGGT		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.439_459delTCCTACGAAGCTCTGAAAGGT		3_prime_UTR_variant	Exon 9 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251476

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

show subpopulations

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461696

Hom.:

AF XY:

0.0000138

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2023	Previously identified in the heterozygous state, without a second variant, in multiple individuals with variable features including muscle weakness/atrophy, hyperCKemia, myalgia, back pain, and reduced calpain protein on western blot analysis and muscle biopsy; however, comprehensive testing, including deletion/duplication analysis, was not completed for all patients and inheritance from an unaffected parent was noted (PMID: 28881388, 18337726, 27259757); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 7 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19556129, 18055493, 10330340, 9150160, 18337726, 27259757, 28881388, 22443334) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 29, 2020	PS3, PS4_moderate, PM2, PM4, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2018	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:3Other:1

not provided, no classification provided	literature only	GeneReviews	-	A single heterozygous in-frame c.643_663del21 pathogenic variant in CAPN3 results in a dominantly inherited form of calpainopathy [Vissing et al 2016]. Of note, this variant has been identified in compound heterozygosity with other pathogenic variants in CAPN3, including c.2362_2363delinsTCATCT, c.550delA, p.Ala45Thr, and p.Asp419Gly [Richard et al 1997, Groen et al 2007, Saenz & Lopez de Munain 2017]. Pathogenic variant most likely the result of a founder effect followed by genetic isolation in populations in Northern European countries including UK, Norway, Sweden, Denmark [Vissing et al 2016] -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2024	This variant, c.643_663del, results in the deletion of 7 amino acid(s) of the CAPN3 protein (p.Ser215_Gly221del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs772579407, gnomAD 0.004%). This variant has been observed in individuals with autosomal dominant and autosomal recessive limb-girdle muscular dystrophy (PMID: 18337726, 27259757, 28881388; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217159). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 28, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 21, 2021	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with limb-girdle muscular dystrophy. Loss of function is a known disease mechanism associated with recessive limb-girdle muscular dystrophy whereas the dominant negative mechanism is suggested for the dominant form of disease associated with milder phenotypes and later age of onset (ClinVar, PMID: 27259757). (I) 0108 - This gene is associated with both recessive and dominant disease. It is predominantly reported as a recessive condition with the dominant condition reported with only a few missense variants and one in-frame deletion (PMID: 27259757, 28881388, 31066050). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated peptidase_C2 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple patients with autosomal dominant limb-girdle muscular dystrophy (MIM#618129) (ClinVar, PMID: 27259757, 28881388). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies have shown that this variant causes a reduction in CAPN3 protein levels in muscle biopsies from affected individuals (PMID: 27259757). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 07, 2025

The NM_000070.3: c.643_663del p.(Ser215_Gly221del) variant in CAPN3 is predicted to cause a change in the length of the protein due to an in-frame deletion of 7 amino acids in a non-repeat region (PM4). This variant has been detected in at least five individuals reported to have autosomal recessive LGMD (PMID: 18055493, 9150160, 22443334; ClinVar SCV000331951.4 internal data communication). In at least one case, the variant was identified in trans with a pathogenic variant (c.2362_2363delinsTCATCT p.(Arg788fsTer14), 1.0 pt, PMID: 9150160), and in at least three patients, the variant was homozygous (1.0 pt, PMID: 22443334, ClinVar SCV000331951.4 internal data communication) (PM3_Strong). At least one of these patients displayed progressive limb girdle muscle weakness and reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 22443334). The variant was also reported to co-segregate with autosomal recessive disease in one affected family member (PP1; PMID: 9150160). The filtering allele frequency of the c.643_663del variant in CAPN3 is 0.000080464 in the European (non-Finnish) population in gnomAD v2.1.1 (the upper threshold of the 95% CI of 4/113756 exome chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (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; 01/07/2025): PM4, PM3_Strong, PP4_Moderate, PP1, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over