rs727503837

Positions:

chr15-42387850-AGTTCTGGAGTGCTCT-A

Variant summary

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

The NM_000070.3(CAPN3):c.598_612del(p.Phe200_Leu204del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 10.0

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:

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 15-42387850-AGTTCTGGAGTGCTCT-A is Pathogenic according to our data. Variant chr15-42387850-AGTTCTGGAGTGCTCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 166786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42387850-AGTTCTGGAGTGCTCT-A is described in Lovd as [Pathogenic]. Variant chr15-42387850-AGTTCTGGAGTGCTCT-A is described in Lovd as [Pathogenic]. Variant chr15-42387850-AGTTCTGGAGTGCTCT-A is described in Lovd as [Pathogenic]. Variant chr15-42387850-AGTTCTGGAGTGCTCT-A is described in Lovd as [Likely_pathogenic]. Variant chr15-42387850-AGTTCTGGAGTGCTCT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAPN3	NM_000070.3 linkuse as main transcript	c.598_612del	p.Phe200_Leu204del	inframe_deletion	4/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2 linkuse as main transcript	c.598_612del	p.Phe200_Leu204del	inframe_deletion	4/23		NP_077320.1
CAPN3	NM_173087.2 linkuse as main transcript	c.598_612del	p.Phe200_Leu204del	inframe_deletion	4/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.598_612del	p.Phe200_Leu204del	inframe_deletion	4/24	1	NM_000070.3	ENSP00000380349	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152180

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251464

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135902

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461882

Hom.:

AF XY:

0.0000206

AC XY:

AN XY:

727242

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CAPN3: PM3:Very Strong, PM2, PM4 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2021	This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2021	In-frame deletion of 5 amino acids in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15733273, 15221789, 16141003, 34720847, 34863162, 30919934, 31589614, 32528171, 9452114, 33107701, 27447704, 16372320, 17236769, 10330340, 10679950, 14981715, 17994539, 15351423, 25135358, 17157502, 34426522, 16100770) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 11, 2022	PP1, PP4_moderate, PM2, PM3_strong, PM4, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 25, 2018	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This variant, c.598_612del, results in the deletion of 5 amino acid(s) of the CAPN3 protein (p.Phe200_Leu204del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771137354, gnomAD 0.005%). This variant has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 9452114, 16141003, 18854869, 25135358). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant limb-girdle muscular dystrophy (PMID: 15733273); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 166786). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 18, 2021	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 16, 2024

- -

CAPN3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

The CAPN3 c.598_612del15 variant is predicted to result in an in-frame deletion (p.Phe200_Leu204del). This variant was reported in the compound heterozygous state or with a second CAPN3 variant in many individuals with autosomal recessive limb girdle muscular dystrophy (Haffner et al. 1998. PubMed ID: 9452114; Stehlíková et al. 2014. PubMed ID: 25135358; Ten Dam et al. 2019. PubMed ID: 30919934; Macias et al. 2021. PubMed ID: 34720847). This variant is reported in 0.0046% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

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