rs149914792

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_000070.3(CAPN3):c.1303G>A(p.Glu435Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 8.06

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a region_of_interest Domain III (size 168) in uniprot entity CAN3_HUMAN there are 132 pathogenic changes around while only 0 benign (100%) in NM_000070.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

PP5

Variant 15-42399601-G-A is Pathogenic according to our data. Variant chr15-42399601-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 282173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42399601-G-A is described in Lovd as [Pathogenic]. Variant chr15-42399601-G-A is described in Lovd as [Pathogenic]. Variant chr15-42399601-G-A 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.1303G>A	p.Glu435Lys	missense_variant	Exon 10 of 24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.1303G>A	p.Glu435Lys	missense_variant	Exon 10 of 23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.1159G>A	p.Glu387Lys	missense_variant	Exon 9 of 21		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.1303G>A	p.Glu435Lys	missense_variant	Exon 10 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 link	n.*1099G>A		non_coding_transcript_exon_variant	Exon 14 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*1099G>A		3_prime_UTR_variant	Exon 14 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000839

AC:

AN:

250332

Hom.:

AF XY:

0.0000887

AC XY:

AN XY:

135344

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

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:

0.0000972

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461388

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000336

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:

0.0000630

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000619

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000298

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:5

May 18, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2022

Eurofins-Biomnis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 435 of the CAPN3 protein (p.Glu435Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 18854869, 20635405, 23553538, 33931068). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 282173). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). For these reasons, this variant has been classified as Pathogenic. -

Jan 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided

Pathogenic:5

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CAPN3: PM1, PM3, PM2:Supporting, PP3 -

Aug 29, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the heterozygous state without a second identifiable CAPN3 variant in an individual with late onset limb girdle muscular dystrophy who had complete calpain-3 deficiency on Western blot (PMID: 15221789); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19226146, 16141003, 31589614, 32528171, 18854869, 11371436, 26363099, 34149409, Aksu2020[casereport], 20635405, 23553538, 35157181, 33931068, 38812636, 15221789) -

Nov 27, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Experiments performed in the paralagous protein, calpain-2 of rat, suggest this variant increases autocatalytic activity, however, it is unclear if this would also be true in calpain-3. 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. -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Mar 20, 2024

Baylor Genetics

Significance: Likely 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

May 07, 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

May 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CAPN3 c.1303G>A (p.Glu435Lys) results in a conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (8.4e-05 vs 0.0032), allowing no conclusion about variant significance. c.1303G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, hyperCkemia, or with clinical symptoms of a neuromuscular disorder or in heterozygous individuals without reported second variant (e.g. Ozyilmaz_2022, Fanin_2009, Saenz_2005, Piluso_2004, Topf_2020, Quick_2021). These data indicate that the variant is likely to be associated with disease. Several publications provide functional evidence suggesting the variant causes significant deficits of calpain-3 quantity and loss of autolytic activity in vitro (e.g. Fanin_2009) or accelerates autolytic degradation, lowering overall enzyme activity (e.g. Granham_2009). The following publications have been ascertained in the context of this evaluation (PMID: 18854869, 19226146, 35157181, 16141003, 33931068, 15689361, 32528171). ClinVar contains an entry for this variant (Variation ID: 282173). Based on the evidence outlined above, the variant was classified as pathogenic. -

Limb-girdle muscular dystrophy

Pathogenic:1

Sep 02, 2021

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1303G>A;p.(Glu435Lys) variant has been published as a pathogenic variant in individuals affected with limb-girdle muscular dystrophy (PMID 15221789; 16141003; 18854869; 20635405; GeneOne, DASA) and ClinVar contains an entry for this variant (Variation ID: 13263) - PS4_moderate; variant is located in a mutational hot spot and/or critical and well-established functional domain (Calpain_III) - PM1; this variant is present in population databases (rs149914792 - gnomAD 0.0092% frequency; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting; variant detected in trans with a pathogenic variant (PMID 18854869; 20635405) - PM3_strong; this variant has been observed to segregate in a family (PMID: 20635405) - PP1; in silico analysis predicts this variant is probably damaging to the protein structure/function - PP3; In summary, the currently available evidence indicates that the variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.055

T;.;.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.1

.;M;.;M

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.9

.;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.021

.;D;D;D

Sift4G

Uncertain

0.029

D;D;D;D

Polyphen

0.99, 1.0, 0.99

.;D;D;D

Vest4

0.97

MVP

0.95

MPC

0.64

ClinPred

0.75

GERP RS

5.4

Varity_R

0.56

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

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