rs1801505

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_000070.3(CAPN3):c.319G>A(p.Glu107Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00855 in 1,613,074 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0087 ( 82 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.16

Publications

21 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 -14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000070.3

BP4

Computational evidence support a benign effect (MetaRNN=0.009398013).

BP6

Variant 15-42384492-G-A is Benign according to our data. Variant chr15-42384492-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.319G>A	p.Glu107Lys	missense_variant	Exon 2 of 24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.319G>A	p.Glu107Lys	missense_variant	Exon 2 of 23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.319G>A	p.Glu107Lys	missense_variant	Exon 2 of 21		NP_775110.1	P20807-2
LOC105370794	XR_932178.3 link	n.*55C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.319G>A	p.Glu107Lys	missense_variant	Exon 2 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 link	n.*115G>A		non_coding_transcript_exon_variant	Exon 6 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*115G>A		3_prime_UTR_variant	Exon 6 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.00672

AC:

1022

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00966

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00853

AC:

2146

AN:

251436

AF XY:

0.00823

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0259

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.00874

AC:

12767

AN:

1460838

Hom.:

Cov.:

AF XY:

0.00847

AC XY:

6158

AN XY:

726816

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33464

American (AMR)

AF:

0.000962

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26128

East Asian (EAS)

AF:

0.000302

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.0252

AC:

1347

AN:

53380

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00985

AC:

10946

AN:

1111088

Other (OTH)

AF:

0.00616

AC:

372

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

626

1252

1877

2503

3129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.00671

AC:

1022

AN:

152236

Hom.:

Cov.:

AF XY:

0.00674

AC XY:

502

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41554

American (AMR)

AF:

0.000850

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000866

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0235

AC:

249

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00966

AC:

657

AN:

68014

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00774

Hom.:

Bravo

AF:

0.00481

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00872

AC:

ExAC

AF:

0.0104

AC:

1266

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 25, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu107Lys in exon 2 of CAPN3: This variant is not expected to have clinical si gnificance because it has been identified in 2.8% (188/66736) of European (Finni sh) chromosomes including 2 homozygotes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs150616566) -

Jan 25, 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. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 05, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CAPN3: BS2 -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Benign:3

Jan 13, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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). 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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

Benign:1

Apr 18, 2022

Fulgent Genetics, Fulgent Genetics

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

0.075

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.10

T;.;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

T;T;T;T

MetaRNN

Benign

0.0094

T;T;T;T

MetaSVM

Uncertain

0.059

MutationAssessor

Benign

0.93

.;L;L;L

PhyloP100

4.2

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

0.83

T;T;T;T

Polyphen

0.0060, 0.011, 0.014

.;B;B;B

Vest4

0.34

MPC

0.18

ClinPred

0.0092

GERP RS

3.6

Varity_R

0.26

gMVP

0.68

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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