rs121434548

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000070.3(CAPN3):c.1469G>A(p.Arg490Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,614,044 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. R490W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.86

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a region_of_interest Domain III (size 168) in uniprot entity CAN3_HUMAN there are 132 pathogenic changes around while only 0 benign (100%) in NM_000070.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42401754-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 15-42401755-G-A is Pathogenic according to our data. Variant chr15-42401755-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42401755-G-A is described in Lovd as [Pathogenic]. Variant chr15-42401755-G-A is described in Lovd as [Pathogenic]. Variant chr15-42401755-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAPN3	NM_000070.3 linkuse as main transcript	c.1469G>A	p.Arg490Gln	missense_variant	11/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2 linkuse as main transcript	c.1469G>A	p.Arg490Gln	missense_variant	11/23		NP_077320.1
CAPN3	NM_173087.2 linkuse as main transcript	c.1325G>A	p.Arg442Gln	missense_variant	10/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.1469G>A	p.Arg490Gln	missense_variant	11/24	1	NM_000070.3	ENSP00000380349	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251152

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000166

AC:

242

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000202

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 490 of the CAPN3 protein (p.Arg490Gln). This variant is present in population databases (rs121434548, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 9266733, 14578192, 15221789, 21984748, 22378277, 27023906, 27431290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as NM_173087:c.1325G>A. ClinVar contains an entry for this variant (Variation ID: 17622). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function. This variant disrupts the p.Arg490 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7720071, 14578192, 15221789, 16372320, 16971480, 17157502, 18563459, 18854869, 19015733, 19226146, 21204801, 25135358, 25252031, 26632398, 27055500). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Arg490Gln variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.006860% (19/276950) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121434548). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg490Gln variant in CAPN3 has been reported in 11 individuals with LGMD and segregated with disease in 2 affected relatives from 1 family (PMID: 16971480, 22378277, 16411092). The presence of this variant in combination with 4 variants (2 reported pathogenic, 2 reported in the literature only) and in 5 individuals with LGMD increases the likelihood that the p.Arg490Gln variant is pathogenic (Variation ID: 17621, 289644). In vitro functional studies provide some evidence that the p.Arg490Gln variant may impact protein function by impairing autolytic activity (PMID: 16971480). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for p.Arg490Gln in an autosomal recessive manner based on evidence from function studies and multiple occurrences with pathogenic CAPN3 variants in individuals with hearing loss). ACMG/AMP Criteria applied: PM2, PP3, PP1, PM3_Strong, PS3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed misssense c.1469G>A(p.Arg490Gln) variant has been reported in homozygous state in multiple patients affected with CAPN3 related disorders (Fanin M, et. al., 2003). Experimental evidence evaluating an impact on protein function demonstrated the variant impairs calpain-3 autolytic activity (Fanin M, et. al., 2007; Fanin M, et. al., 2005). This variant is present with an allele frequency of 0.007% in gnomAD Exomes database. This variant has been reported 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 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 490 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2021	Published functional studies demonstrate disruption of protein function (Fanin et al., 2003); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17994539, 18055493, 22378277, 16411092, 16141003, 21984748, 9266733, 15725583, 16650086, 15221789, 10330340, 14578192, 20635405, 27023906, 27431290, 16971480, 34426522, 30028523, 32140910, 31589614, 32721234, 32528171) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2017	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 14, 2024

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 11, 2022

Variant summary: CAPN3 c.1469G>A (p.Arg490Gln) results in a conservative amino acid change located in the Calpain subdomain III (IPR033883) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251152 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (6.8e-05 vs 0.0032), allowing no conclusion about variant significance. c.1469G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Richard_1999, Fanin_2007). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant impairs calpain-3 autolytic activity (Fanin_2007). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;.;.;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

.;M;.;M

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.9

.;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.96

MutPred

0.94

.;Loss of MoRF binding (P = 0.0262);.;Loss of MoRF binding (P = 0.0262);

MVP

0.97

MPC

0.68

ClinPred

0.92

GERP RS

4.7

Varity_R

0.90

gMVP

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over