rs146923842

Positions:

chr15-42410660-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1PM5PP5BP4BS2

The NM_000070.3(CAPN3):c.2257G>A(p.Asp753Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000912 in 1,613,422 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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. D753K?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00093 ( 2 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:14

Conservation

PhyloP100: 5.79

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a domain EF-hand 3 (size 35) in uniprot entity CAN3_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000070.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42410659-CG-CAA is described in Lovd as [Pathogenic].

PP5

Variant 15-42410660-G-A is Pathogenic according to our data. Variant chr15-42410660-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281081.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=12}. Variant chr15-42410660-G-A is described in Lovd as [Pathogenic]. Variant chr15-42410660-G-A is described in Lovd as [Pathogenic]. Variant chr15-42410660-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.08944106). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3 linkuse as main transcript	c.2257G>A	p.Asp753Asn	missense_variant	21/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.2257G>A	p.Asp753Asn	missense_variant	21/24	1	NM_000070.3	ENSP00000380349	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000785

AC:

197

AN:

250800

Hom.:

AF XY:

0.000797

AC XY:

108

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000929

AC:

1357

AN:

1461252

Hom.:

Cov.:

AF XY:

0.000898

AC XY:

653

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000986

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.000318

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.000961

GnomAD4 genome

AF:

0.000756

AC:

115

AN:

152170

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00112

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000758

AC:

EpiCase

AF:

0.00207

EpiControl

AF:

0.00155

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:1Uncertain:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 09, 2019	Across a selection of the available literature, the CAPN3 c.2257G>A (p.Arg753Asn) is identified in six probands described to have limb girdle muscular dystrophy in a heterozygous state and five probands in a compound heterozygous state (Fanin et al. 2004; Piluso et al. 2005; Saenz et al. 2005; Todorova et al. 2007; Fanin et al. 2009). The p.Arg753Asn variant absent from at least 400 controls and is reported at a frequency of 0.00118 in the European (non-Finnish) population of the Exome Aggregation Consortium. Todorova et al. (2007) noted that the variant, when observed in a heterozygous state in probands with limb girdle muscular dystrophy, seemed to confer a later onset and milder phenotype. Based on the evidence, the p.Asp753Asn variant is classified as likely pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_000070.2(CAPN3):c.2257G>A(D753N) is classified as a variant of uncertain significance in the context of calpainopathy. Sources cited for classification include the following: PMID 17318636, 17994539, 17897828, 18854869, 20044116, 16141003, 27884173 and 30564623. Classification of NM_000070.2(CAPN3):c.2257G>A(D753N) is based on the following criteria: At this time, there is insufficient or conflicting evidence to classify this variant as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 753 of the CAPN3 protein (p.Asp753Asn). This variant is present in population databases (rs146923842, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with limb girdle muscular dystrophy (PMID: 16141003, 18854869). ClinVar contains an entry for this variant (Variation ID: 281081). 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 not expected to disrupt CAPN3 protein function. 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. -

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 23, 2024	PM3, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2024	Reported, without a second identifiable CAPN3 variant, in an individual with LGMD2A who had complete calpain-3 deficiency on Western blot (PMID: 15221789); Reported in the heterozygous and compound heterozygous state in association with LGMD2A; however, parental testing was not completed and functional characterization of the variant was not performed (PMID: 16141003, 15689361, 17318636); Reported previously in five patients with LGMD and two of these patients harbored a second variant (phase unknown). No further clinical or segregation information was provided (PMID: 18854869, 30564623); 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: 17994539, 15689361, 31937337, 17318636, 27884173, 32403337, 31931849, 30564623, Koken_2022[Poster], 32528171, 34720847, 35157181, 38391941, 16141003, 18854869, 36575883, 15221789) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CAPN3 p.D753N variant was identified in the heterozygous or compound heterozygous state in 9 of 2194 proband chromosomes (frequency: 0.004) from individuals with Limb girdle muscular dystrophy (LGMD) type 2A (LGMD2A) and unspecified muscular dystrophy (Todorova_2007_PMID:17318636; Piluso_2005_PMID:16141003; Fanin_2009_PMID:18854869). The variant was identified in dbSNP (ID: rs146923842), ClinVar (classified as uncertain significance by EGL Genetics, GeneDx and Invitae and as likely pathogenic by Counsyl and Illumina) and LOVD 3.0 (classified as pathogenic and a VUS). The variant was identified in control databases in 210 of 282180 chromosomes (0 homozygous) at a frequency of 0.0007442 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 39 of 35324 chromosomes (freq: 0.001104), European (non-Finnish) in 142 of 128804 chromosomes (freq: 0.001102), Ashkenazi Jewish in 8 of 10354 chromosomes (freq: 0.000773), Other in 4 of 7212 chromosomes (freq: 0.000555), European (Finnish) in 6 of 25108 chromosomes (freq: 0.000239), East Asian in 4 of 19914 chromosomes (freq: 0.000201), South Asian in 4 of 30576 chromosomes (freq: 0.000131), and African in 3 of 24888 chromosomes (freq: 0.000121). The p.Asp661 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Fanin et al. (2009) identified the p.D753N variant in two heterozygous and two compound heterozygous patients with Limb girdle muscular dystrophy; these patients had varying degrees of calpain levels and autolytic activity ranging from normal to absent (Fanin_2009_PMID:18854869). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 25, 2023	PM3_supporting -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 29, 2022	- -

CAPN3-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DASA

Feb 05, 2022

The c.2257G>A;p.(Asp753Asn) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 31517061; 18854869) - PS4_moderate. The variant is present at low allele frequencies population databases (rs146923842 – gnomAD 0.007563%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asp753Asn) was detected in trans with a pathogenic variant (PMID: 31517061; 18854869) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 22, 2023

Variant summary: CAPN3 c.2257G>A (p.Asp753Asn) results in a conservative amino acid change located in the EF-hand domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 250800 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00079 vs 0.0032), allowing no conclusion about variant significance. c.2257G>A has been reported in the literature in the heterozygous or compound heterozygous state in individuals affected with Limb-Girdle Muscular Dystrophy without strong evidence for causality (eg. Fanin_2004, Piluso_2005, Saenz_2005, Todorova_2007, Guglieri_2008, Fanin_2009, Nallamilli_2018, Macias_2021, Ozyilmaz_2022). These reports do not provide unequivocal conclusions about association of the variant with autosomal recessive Limb-Girdle Muscular Dystrophy. 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: 30564623, 17994539, 31931849, 18854869, 16141003, 15221789, 32528171, 15689361, 32403337, 34720847, 31517061, 17318636, 35157181). Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=8) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.022

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

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

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.089

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.2

.;.;.;L;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.5

.;N;N;N;N;N;N;D;N;N;N;N

REVEL

Pathogenic

0.65

Sift

Benign

0.44

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

Sift4G

Benign

0.45

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

1.0

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

Vest4

0.61

MVP

0.97

MPC

0.62

ClinPred

0.19

GERP RS

4.5

Varity_R

0.62

gMVP

0.64

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