chr15-42388934-TGGTTCCTACGAAGCTCTGAAA-T

Position:

chr15-42388934-TGGTTCCTACGAAGCTCTGAAA-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM4PP3PP5_Very_Strong

The NM_000070.3(CAPN3):c.643_663del(p.Ser215_Gly221del) variant causes a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G214G) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O: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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000070.3

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 criteria_provided_multiple_submitters_no_conflicts, 2 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/exons	MANE
CAPN3	NM_000070.3 linkuse as main transcript	c.643_663del	p.Ser215_Gly221del	inframe_deletion	5/24	ENST00000397163.8
CAPN3	NM_024344.2 linkuse as main transcript	c.643_663del	p.Ser215_Gly221del	inframe_deletion	5/23
CAPN3	NM_173087.2 linkuse as main transcript	c.643_663del	p.Ser215_Gly221del	inframe_deletion	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.643_663del	p.Ser215_Gly221del	inframe_deletion	5/24	1	NM_000070.3	P2	P20807-1

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:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

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	Eurofins Ntd Llc (ga)	Mar 30, 2018	- -
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	Revvity Omics, Revvity	May 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 29, 2020	PS3, PS4_moderate, PM2, PM4, PP1 -

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	Oct 30, 2023	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; Invitae). 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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 21, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 28, 2017	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2024	- -

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