rs199625801

Positions:

chr15-42399590-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP3

The NM_000070.3(CAPN3):c.1292T>C(p.Val431Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000088 in 1,613,756 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V431L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.25

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 Uncertain_significance. Variant got 5 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, 7 uncertain in NM_000070.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42399589-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAPN3	NM_000070.3 linkuse as main transcript	c.1292T>C	p.Val431Ala	missense_variant	10/24	ENST00000397163.8
CAPN3	NM_024344.2 linkuse as main transcript	c.1292T>C	p.Val431Ala	missense_variant	10/23
CAPN3	NM_173087.2 linkuse as main transcript	c.1148T>C	p.Val383Ala	missense_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.1292T>C	p.Val431Ala	missense_variant	10/24	1	NM_000070.3	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251176

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135770

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:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000937

AC:

137

AN:

1461638

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727102

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:

0.000121

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 22, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 431 of the CAPN3 protein (p.Val431Ala). This variant is present in population databases (rs199625801, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 418108). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2017	The maternally inherited V431A variant in the CAPN3 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. However, a missense mutation at the same residue (V431M) has been reported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson et al., 2009). The V431A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V431A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (N434I, E435K) have been reported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson et al., 2009), supporting the functional importance of this region of the protein. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we interpret V431A as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 01, 2024

Variant summary: CAPN3 c.1292T>C (p.Val431Ala) results in a non-conservative amino acid change located in the catalytic domain (IPR001300) 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 4.4e-05 in 251176 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (4.4e-05 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1292T>C in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 418108). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

T;.;.;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Uncertain

0.44

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.72

REVEL

Pathogenic

0.75

Sift4G

Benign

0.098

T;T;T;T

Polyphen

1.0, 0.99, 1.0

.;D;D;D

Vest4

0.81

MVP

0.94

MPC

0.69

ClinPred

0.57

GERP RS

5.4

Varity_R

0.29

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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