rs17592

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000070.3(CAPN3):c.479C>G(p.Ala160Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,612,222 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A160T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 56 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 42 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 3.31

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015996903).

BP6

Variant 15-42386266-C-G is Benign according to our data. Variant chr15-42386266-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0146 (2223/152300) while in subpopulation AFR AF = 0.0511 (2123/41562). AF 95% confidence interval is 0.0493. There are 56 homozygotes in GnomAd4. There are 1038 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 56 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.479C>G	p.Ala160Gly	missense_variant	Exon 3 of 24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.479C>G	p.Ala160Gly	missense_variant	Exon 3 of 23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.479C>G	p.Ala160Gly	missense_variant	Exon 3 of 21		NP_775110.1	P20807-2
LOC105370794	XR_932178.3 link	n.-235G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.479C>G	p.Ala160Gly	missense_variant	Exon 3 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 link	n.*275C>G		non_coding_transcript_exon_variant	Exon 7 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*275C>G		3_prime_UTR_variant	Exon 7 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2218

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0511

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

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:

0.000118

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00367

AC:

923

AN:

251420

AF XY:

0.00257

show subpopulations

Gnomad AFR exome

AF:

0.0515

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00139

AC:

2030

AN:

1459922

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

866

AN XY:

726480

show subpopulations

African (AFR)

AF:

0.0506

AC:

1692

AN:

33416

American (AMR)

AF:

0.00226

AC:

101

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000104

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000423

AC:

AN:

1110274

Other (OTH)

AF:

0.00292

AC:

176

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

104

209

313

418

522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.0146

AC:

2223

AN:

152300

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1038

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0511

AC:

2123

AN:

41562

American (AMR)

AF:

0.00458

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68026

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

106

211

317

422

528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00208

Hom.:

Bravo

AF:

0.0157

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0483

AC:

213

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00451

AC:

548

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 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 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

- -

Mar 01, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Benign:5

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign, for Muscular dystrophy, limb-girdle, type 2a, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 07-20-2006 by Athena Diagnostics Inc. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Limb-girdle muscular dystrophy, recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;.;.;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

D;D;D;D

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Uncertain

0.085

MutationAssessor

Pathogenic

3.5

.;H;H;H

PhyloP100

3.3

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.38, 0.032, 0.43

.;B;B;B

Vest4

0.48

MVP

0.94

MPC

0.29

ClinPred

0.084

GERP RS

6.1

Varity_R

0.85

gMVP

0.65

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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