rs190793093

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM5PP3_ModeratePP5

The NM_000070.3(CAPN3):c.2093G>A(p.Arg698His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,144 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R698C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:8

Conservation

PhyloP100: 10.0

Publications

4 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: Uncertain_significance. The variant received 5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42409972-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285572.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

PP5

Variant 15-42409973-G-A is Pathogenic according to our data. Variant chr15-42409973-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 499036.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2093G>A	p.Arg698His	missense_variant	Exon 19 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CAPN3	ENST00000397163.8 link	c.2093G>A	p.Arg698His	missense_variant	Exon 19 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1 link	c.98G>A	p.Arg33His	missense_variant	Exon 6 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1 link	c.98G>A	p.Arg33His	missense_variant	Exon 6 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1 link	c.98G>A	p.Arg33His	missense_variant	Exon 7 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1 link	c.98G>A	p.Arg33His	missense_variant	Exon 6 of 11			ENSP00000501112.1
ENSG00000258461	ENST00000495723.1 link	n.*2529G>A		non_coding_transcript_exon_variant	Exon 21 of 26	2		ENSP00000492063.1
CAPN3	ENST00000673743.1 link	c.-5G>A		5_prime_UTR_variant	Exon 6 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1 link	n.*2529G>A		3_prime_UTR_variant	Exon 21 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251334

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1459940

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726266

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4296

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111862

Other (OTH)

AF:

0.0000166

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000460

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41528

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Uncertain:4

Sep 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 698 of the CAPN3 protein (p.Arg698His). This variant is present in population databases (rs190793093, gnomAD 0.01%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 25135358, 30564623; internal data). ClinVar contains an entry for this variant (Variation ID: 499036). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg698 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10330340, 15689361, 16411092, 21204801). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 15, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 16, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1Uncertain:2

Jan 23, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 08, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16411092, 21204801, 10330340, 15689361, 37526466, 25135358, 30564623) -

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

Pathogenic:1

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Sep 01, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CAPN3 c.2093G>A (p.Arg698His) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. This alters a highly conserved amino acid in which other missense changes have been found in association with disease (HGMD), suggesting this may be a clinically important residue. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251334 control chromosomes (gnomAD). c.2093G>A has been reported in the literature in two individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Stehlikova_2014, Nallamilli_2018), and one was reported as compound heterozygous with a pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25135358, 30564623). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Uncertain:1

Aug 07, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.098

T;.;.;D;.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

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

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.85

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

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

3.2

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

PhyloP100

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.95

Sift

Uncertain

0.025

.;D;D;D;D;D;D;.;D;D;D;T

Sift4G

Uncertain

0.042

D;D;D;T;T;T;D;D;D;D;D;D

Polyphen

1.0

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

Vest4

0.96

MVP

0.97

MPC

0.70

ClinPred

0.95

GERP RS

4.8

Varity_R

0.58

gMVP

0.72

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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