rs200379491

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM5PP3PP5_Very_StrongBP4

The NM_000070.3(CAPN3):c.2120A>G(p.Asp707Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. D707H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.48

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 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000070.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42410431-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290334.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 15-42410432-A-G is Pathogenic according to our data. Variant chr15-42410432-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42410432-A-G is described in Lovd as [Pathogenic]. Variant chr15-42410432-A-G is described in Lovd as [Pathogenic]. Variant chr15-42410432-A-G is described in Lovd as [Likely_pathogenic]. Variant chr15-42410432-A-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.39079383). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3 linkuse as main transcript	c.2120A>G	p.Asp707Gly	missense_variant	20/24	ENST00000397163.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.2120A>G	p.Asp707Gly	missense_variant	20/24	1	NM_000070.3	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

251460

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00207

Gnomad SAS 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:

0.0000438

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00156

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00213

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 06, 2020	NM_000070.2(CAPN3):c.2120A>G(D707G) is classified as pathogenic in the context of calpainopathy. Sources cited for classification include the following: PMID 25079074, 26632398, 11525884 and 27066573. Classification of NM_000070.2(CAPN3):c.2120A>G(D707G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 707 of the CAPN3 protein (p.Asp707Gly). This variant is present in population databases (rs200379491, gnomAD 0.2%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10567047, 11525884, 25252031, 26632398). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 468648). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Medical Genetic Department, The Affiliated Hospital of Qingdao University	Dec 01, 2020	The missense variant c.2120A>G/p.(Asp707Gly) in exon 20 resulted in a single-nucleotide polymorphism (A to G) at site 2120 in the coding region of CAPN3 (NM_000070.2), which introduced an aspartic acid residue that replaced a glycine in codon 707 (Fig. 3A). This variant was previously reported in multiple (>10) homozygous or compound heterozygous patients with LGMDs (PM3-PVS), which co-segregated within a family (PP1-PM). The normal population database includes this variant; its frequency is 0.0148% (42/282854, gnomAD) (PM2); bioinformatics analysis software SIFT, PolyPhen2, and Variant Taster consistently predicted the variant to be harmful (PP3). In addition, the variant is included in ClinVar as a â€œpathogenic/suspected pathogenic variant.â€ According to available evidence, the variant is defined as pathogenic (PM3-PVS+PM2+PP1-PM+PP3) based on the 2015 ACMG guidelines for sequence variant interpretation.The WES of this patient revealed compound heterozygous variants in CAPN3, c.2120A>G/p. (Asp707Gly) in exon 20 and c.2201_2202delAT/p.(Tyr734) in exon 21, which were inherited from his parents and absent from 200 control individuals of similar ethnic origin, indicating that these variants are the pathogenic triggers of the LGMDR1 phenotype. In summary, we observed a sporadic male case of LGMDR1 and identified two compound heterozygous variants in CAPN3, namely c.2120A>G/p. (Asp707Gly) and c.2201_2202delAT/ p.(Tyr734)), which co-segregated with the LGMDR1 phenotypes in the probandâ€™s family. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 26, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Oct 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000468648, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 26632398, PM3_S). A different missense change at the same codon has been reported to be associated with CAPN3 related disorder (ClinVar ID: VCV000290334, PM5_P).The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3CNET: 0.862, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000148, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2016	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

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

Nov 16, 2021

- -

CAPN3-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

The CAPN3 c.2120A>G variant is predicted to result in the amino acid substitution p.Asp707Gly. This variant has been reported with a second CAPN3 variant or in the homozygous state in individuals with limb-girdle muscular dystrophy (see, for example, Minami et al. 1999. PubMed ID: 10567047; Chae et al. 2001. PubMed ID: 11525884; Park et al. 2016. PubMed ID: 26632398). This variant is reported in 0.21% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.39

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

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.2

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.0

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

REVEL

Pathogenic

0.97

Sift

Benign

0.052

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

Sift4G

Uncertain

0.0070

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

Polyphen

1.0

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

Vest4

0.89

MVP

0.98

MPC

0.68

ClinPred

0.58

GERP RS

5.0

Varity_R

0.87

gMVP

0.74

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