rs1801449

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/21 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:17

Conservation

PhyloP100: 5.24

Publications

30 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
muscular dystrophy, limb-girdle, autosomal dominant 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
muscular dystrophy, limb-girdle, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CAPN3 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 Benign/Likely_benign. ClinVar VariationId is 92420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.706G>A	p.Ala236Thr	missense_variant	Exon 5 of 24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.706G>A	p.Ala236Thr	missense_variant	Exon 5 of 23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.706G>A	p.Ala236Thr	missense_variant	Exon 5 of 21		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.706G>A	p.Ala236Thr	missense_variant	Exon 5 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 link	n.*502G>A		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*502G>A		3_prime_UTR_variant	Exon 9 of 26	2		ENSP00000492063.1	A0A1W2PQD3

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

GnomAD2 exomes

AF:

0.113

AC:

28526

AN:

251464

AF XY:

0.106

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 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

African (AFR)

AF:

0.651

AC:

21794

AN:

33470

American (AMR)

AF:

0.0779

AC:

3485

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2776

AN:

26134

East Asian (EAS)

AF:

0.112

AC:

4431

AN:

39700

South Asian (SAS)

AF:

0.138

AC:

11891

AN:

86248

European-Finnish (FIN)

AF:

0.0950

AC:

5073

AN:

53420

Middle Eastern (MID)

AF:

0.109

AC:

630

AN:

5756

European-Non Finnish (NFE)

AF:

0.0404

AC:

44955

AN:

1111888

Other (OTH)

AF:

0.101

AC:

6098

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

4582

9164

13745

18327

22909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2052

4104

6156

8208

10260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.222

AC:

33763

AN:

151982

Hom.:

8667

Cov.:

AF XY:

0.219

AC XY:

16236

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.630

AC:

26078

AN:

41362

American (AMR)

AF:

0.0986

AC:

1507

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

360

AN:

3470

East Asian (EAS)

AF:

0.118

AC:

606

AN:

5150

South Asian (SAS)

AF:

0.136

AC:

654

AN:

4826

European-Finnish (FIN)

AF:

0.0960

AC:

1016

AN:

10586

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0465

AC:

3162

AN:

67984

Other (OTH)

AF:

0.167

AC:

353

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

809

1618

2428

3237

4046

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0975

Hom.:

11262

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:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Jan 14, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 04, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 10, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Benign:6

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Apr 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Limb-girdle muscular dystrophy, recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

MutationAssessor

Benign

-1.1

.;N;N;N

PhyloP100

5.2

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over