rs1801449

Positions:

chr15-42389001-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000070.3(CAPN3):c.706G>A(p.Ala236Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0836 in 1,613,710 control chromosomes in the GnomAD database, including 19,097 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A236A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 8667 hom., cov: 31)

Exomes 𝑓: 0.069 ( 10430 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 5.24

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 Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000070.3

BP4

Computational evidence support a benign effect (MetaRNN=3.6192458E-5).

BP6

Variant 15-42389001-G-A is Benign according to our data. Variant chr15-42389001-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42389001-G-A is described in Lovd as [Benign]. Variant chr15-42389001-G-A is described in Lovd as [Likely_benign]. Variant chr15-42389001-G-A is described in Lovd as [Pathogenic]. Variant chr15-42389001-G-A is described in Lovd as [Pathogenic]. Variant chr15-42389001-G-A is described in Lovd as [Likely_pathogenic]. Variant chr15-42389001-G-A is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAPN3	NM_000070.3 linkuse as main transcript	c.706G>A	p.Ala236Thr	missense_variant	5/24	ENST00000397163.8
CAPN3	NM_024344.2 linkuse as main transcript	c.706G>A	p.Ala236Thr	missense_variant	5/23
CAPN3	NM_173087.2 linkuse as main transcript	c.706G>A	p.Ala236Thr	missense_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.706G>A	p.Ala236Thr	missense_variant	5/24	1	NM_000070.3	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

33668

AN:

151864

Hom.:

8632

Cov.:

show subpopulations

Gnomad AFR

AF:

0.630

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0989

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.135

Gnomad FIN

AF:

0.0960

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.169

GnomAD3 exomes

AF:

0.113

AC:

28526

AN:

251464

Hom.:

4356

AF XY:

0.106

AC XY:

14383

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.643

Gnomad AMR exome

AF:

0.0761

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.128

Gnomad SAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.0946

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0836

GnomAD4 exome

AF:

0.0692

AC:

101133

AN:

1461728

Hom.:

10430

Cov.:

AF XY:

0.0698

AC XY:

50733

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.651

Gnomad4 AMR exome

AF:

0.0779

Gnomad4 ASJ exome

AF:

0.106

Gnomad4 EAS exome

AF:

0.112

Gnomad4 SAS exome

AF:

0.138

Gnomad4 FIN exome

AF:

0.0950

Gnomad4 NFE exome

AF:

0.0404

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.222

AC:

33763

AN:

151982

Hom.:

8667

Cov.:

AF XY:

0.219

AC XY:

16236

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.630

Gnomad4 AMR

AF:

0.0986

Gnomad4 ASJ

AF:

0.104

Gnomad4 EAS

AF:

0.118

Gnomad4 SAS

AF:

0.136

Gnomad4 FIN

AF:

0.0960

Gnomad4 NFE

AF:

0.0465

Gnomad4 OTH

AF:

0.167

Alfa

AF:

0.0794

Hom.:

4028

Bravo

AF:

0.241

TwinsUK

AF:

0.0418

AC:

155

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.621

AC:

2737

ESP6500EA

AF:

0.0497

AC:

427

ExAC

AF:

0.124

AC:

15028

Asia WGS

AF:

0.143

AC:

497

AN:

3476

EpiCase

AF:

0.0481

EpiControl

AF:

0.0458

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Ala236Thr in exon 5 of CAPN3: This variant is not expected to have clinical si gnificance because it has been identified in 62% (2737/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs1801449). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 10, 2016	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Benign:6

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Limb-girdle muscular dystrophy, recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.060

T;.;.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.52

T;T;T;T

MetaRNN

Benign

0.000036

T;T;T;T

MetaSVM

Benign

-0.96

MutationTaster

Benign

0.96

P;P;P;P;P

PrimateAI

Uncertain

0.73

PROVEAN

Benign

1.2

N;N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.87

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;B;B

Vest4

0.058

MPC

0.14

ClinPred

0.013

GERP RS

5.4

Varity_R

0.56

gMVP

0.51

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