rs149914792

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E435D) has been classified as Uncertain significance.

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:12

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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/exons	MANE
CAPN3	NM_000070.3 linkuse as main transcript	c.1303G>A	p.Glu435Lys	missense_variant	10/24	ENST00000397163.8
CAPN3	NM_024344.2 linkuse as main transcript	c.1303G>A	p.Glu435Lys	missense_variant	10/23
CAPN3	NM_173087.2 linkuse as main transcript	c.1159G>A	p.Glu387Lys	missense_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.1303G>A	p.Glu435Lys	missense_variant	10/24	1	NM_000070.3	P2	P20807-1

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2019	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Results on protein functions were inconclusive. Inconclusive segregation with disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CAPN3: PM1, PM3, PM2:Supporting, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2023	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 (Fanin et al., 2004).; 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, 15221789) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 26, 2022	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Oct 20, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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). 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 24, 2023

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2022

- -

Limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Sep 02, 2021

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.85

REVEL

Pathogenic

0.81

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