15-42410460-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000070.3(CAPN3):c.2148G>T(p.Glu716Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 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: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 0.726

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 20) in uniprot entity CAN3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000070.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 15-42410460-G-T is Pathogenic according to our data. Variant chr15-42410460-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 285340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42410460-G-T is described in Lovd as [Pathogenic]. Variant chr15-42410460-G-T is described in Lovd as [Pathogenic]. Variant chr15-42410460-G-T 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.2148G>T	p.Glu716Asp	missense_variant	Exon 20 of 24	ENST00000397163.8	NP_000061.1	P20807-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.2148G>T	p.Glu716Asp	missense_variant	Exon 20 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.153G>T	p.Glu51Asp	missense_variant	Exon 7 of 11			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.153G>T	p.Glu51Asp	missense_variant	Exon 7 of 11			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.153G>T	p.Glu51Asp	missense_variant	Exon 8 of 12			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.153G>T	p.Glu51Asp	missense_variant	Exon 7 of 11			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.51G>T	p.Glu17Asp	missense_variant	Exon 7 of 11			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2584G>T		non_coding_transcript_exon_variant	Exon 22 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*2584G>T		3_prime_UTR_variant	Exon 22 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000413

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

May 31, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E716D missense variant has been reported previously in a patient with LGMD2A who also harbored a second CAPN3 variant; however phase was undetermined (Saenz et al., 2005). Functional studies demonstrate a complete loss of the CAPN3 protein in this patient (Saenz et al., 2005). The E716D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E716D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. Additionally, a missense variant in a nearby residue (L712F) has been reported in the Human Gene Mutation Database in association with LGMD (Stenson et al., 2014). Therefore, we interpret E716D as a pathogenic variant. -

Mar 05, 2018

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:2Uncertain:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 716 of the CAPN3 protein (p.Glu716Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361; Invitae). 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: 285340). 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%. 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. -

Oct 07, 2017

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jul 14, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3, PP2, PP3, PP5 -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Oct 31, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

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

Pathogenic:1

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.074

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

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.8

.;.;.;M;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.7

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

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.0090

D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0

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

Vest4

0.59

MutPred

0.94

.;.;.;Gain of MoRF binding (P = 0.1041);.;.;.;.;.;.;.;.;

MVP

0.94

MPC

0.25

ClinPred

0.98

GERP RS

2.7

Varity_R

0.78

gMVP

0.83

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

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