rs553169803

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000673743(CAPN3):c.-52G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,350,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000076 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CAPN3
ENST00000673743 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.22

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25755763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2041G>A	p.Val681Met	missense_variant	Exon 18 of 24	ENST00000397163.8	NP_000061.1	P20807-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000673743 link	c.-52G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 5 of 11			ENSP00000500989.1	A0A669KAX6
CAPN3	ENST00000397163.8 link	c.2041G>A	p.Val681Met	missense_variant	Exon 18 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.46G>A	p.Val16Met	missense_variant	Exon 5 of 11			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.46G>A	p.Val16Met	missense_variant	Exon 5 of 11			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.46G>A	p.Val16Met	missense_variant	Exon 6 of 12			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.46G>A	p.Val16Met	missense_variant	Exon 5 of 11			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743 link	c.-52G>A		5_prime_UTR_variant	Exon 5 of 11			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2477G>A		non_coding_transcript_exon_variant	Exon 20 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*2477G>A		3_prime_UTR_variant	Exon 20 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.0000762

AC:

AN:

131208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000268

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000790

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251162

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1219574

Hom.:

Cov.:

AF XY:

0.0000197

AC XY:

AN XY:

607754

show subpopulations

Gnomad4 AFR exome

AF:

0.0000746

Gnomad4 AMR exome

AF:

0.0000510

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000451

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000509

Gnomad4 NFE exome

AF:

0.0000138

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000762

AC:

AN:

131268

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

62192

show subpopulations

Gnomad4 AFR

AF:

0.000112

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000267

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000790

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000389

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Uncertain:2

Mar 11, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 681 of the CAPN3 protein (p.Val681Met). This variant is present in population databases (rs553169803, gnomAD 0.005%). 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: 536514). 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:1

Nov 16, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

T;.;.;T;.;.;.;.;.;.;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;.;D;.;D;.;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.26

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.019

MutationAssessor

Benign

1.7

.;.;.;L;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

.;N;N;N;N;N;N;.;N;N;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.053

.;T;T;T;T;T;D;.;D;D;D;D

Sift4G

Benign

0.24

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.99, 0.99

.;D;D;D;.;.;.;.;.;.;.;.

Vest4

0.54

MVP

0.91

MPC

0.50

ClinPred

0.44

GERP RS

4.8

Varity_R

0.26

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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