rs587780290

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000070.3(CAPN3):c.2243G>A(p.Arg748Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,734 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R748L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 10.0

Publications

26 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: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000070.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42410645-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 548138.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 15-42410646-G-A is Pathogenic according to our data. Variant chr15-42410646-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 128570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2243G>A	p.Arg748Gln	missense_variant	Exon 21 of 24	ENST00000397163.8	NP_000061.1	P20807-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.2243G>A	p.Arg748Gln	missense_variant	Exon 21 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.248G>A	p.Arg83Gln	missense_variant	Exon 8 of 11			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.248G>A	p.Arg83Gln	missense_variant	Exon 8 of 11			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.248G>A	p.Arg83Gln	missense_variant	Exon 9 of 12			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.248G>A	p.Arg83Gln	missense_variant	Exon 8 of 11			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.146G>A	p.Arg49Gln	missense_variant	Exon 8 of 11			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2679G>A		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*2679G>A		3_prime_UTR_variant	Exon 23 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251118

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111898

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.0000197

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41366

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000139

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:8

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 748 of the CAPN3 protein (p.Arg748Gln). This variant is present in population databases (rs587780290, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 9762961, 9777948, 10330340, 12461690, 15689361, 18563459, 18854869, 19015733, 22443334, 26404900, 27020652, 30028523). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128570). 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%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). For these reasons, this variant has been classified as Pathogenic. -

Nov 07, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2017

Counsyl

Significance:Pathogenic

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. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Arg748Gln variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD) This variant has been identified in 0.01455% (5/34372) of Latino chromosomes and 0.004166% (1/24006) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587780290). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. One study that examined a rat model with an analagous protein suggested that this variant affects protein catalytic activity (PMID: 19226146). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enought to determine pathogenicity. The p.Arg748Gln variant in CAPN3 has been reported in many individuals with LGMD in the homozygous and compound heterozygous states in ClinVar and the literature (Variation ID: 128570). This variant segregated with disease in 2 affected relatives from 1 family (PMID: 9150160). There are many reports of individuals with LGMD and this variant (in either the homozygous or compound heterozygous state) in ClinVar and the literature. Animal models in rats have shown that this variant causes LGMD via a deleterious effect on calpain protein catalytic activity (PMID: 19226146). In summary, the p.Arg748Gln variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PP3, PS3, PP1, PM3_Strong (Richards 2015). -

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense c.2243G>A p.Arg748Gln variant in CAPN3 gene has been previously reported in homozygous/ compound heterozygous states in multiple individuals affected with autosomal recessive limb-girdle muscular dystrophy Arrigoni et al., 2018; Fadaee et al., 2016; Hauerslev et al., 2012; Sáenz et al., 2011; Fanin et al., 2009. It has also been observed to segregate with disease in related individuals Fadaee et al., 2013; Richard et al., 1997. Experimental studies have shown that this missense change affects CAPN3 function Garnham et al., 2009. This variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/ Pathogenic multiple submissions. Multiple lines of computational evidence Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg748Gln in CAPN3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 748 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:5

Feb 07, 2024

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been identified in multiple individuals with autosomal recessive Limb-girdle muscular dystrophy and segregates with disease in multiple families. The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 19226146, 22006685) -

Nov 10, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 18, 2024

GeneDx

Significance: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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18563459, 19364062, 10330340, 9762961, 22443334, 926673, 27234031, 36066420, 30056071, 19226146, 21204801, 22006685, 25525159, 27020652, 25987458, 18854869, 15689361, 9150160, 30028523, 30919934, 31589614, 34426522, 32528171, 35314707, 31069529, 35169782, 35723113, 25512505, 31980526, 32668095, 32403337, 37526466, 38374194) -

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Mar 13, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Mar 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Abnormality of the musculature

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.073

T;.;.;T;.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

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

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.97

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

MetaSVM

Uncertain

-0.028

MutationAssessor

Uncertain

2.1

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

PhyloP100

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.6

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

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.96

MutPred

0.92

.;.;.;Gain of disorder (P = 0.1607);.;.;.;.;.;.;.;.;

MVP

0.89

MPC

0.68

ClinPred

0.98

GERP RS

4.5

Varity_R

0.88

gMVP

0.87

Mutation Taster

=1/99

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over