rs767106920

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_000070.3(CAPN3):c.1099G>A(p.Gly367Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,408,370 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. G367delinsNKNRC) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 9.63

Publications

6 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: Likely_pathogenic. The variant received 7 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, 7 uncertain in NM_000070.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 15-42394325-G-A is Pathogenic according to our data. Variant chr15-42394325-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468639.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.1099G>A	p.Gly367Ser	missense_variant	Exon 8 of 24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.1099G>A	p.Gly367Ser	missense_variant	Exon 8 of 23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.955G>A	p.Gly319Ser	missense_variant	Exon 7 of 21		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.1099G>A	p.Gly367Ser	missense_variant	Exon 8 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 link	n.*895G>A		non_coding_transcript_exon_variant	Exon 12 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*895G>A		3_prime_UTR_variant	Exon 12 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000536

AC:

AN:

167974

AF XY:

0.0000451

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000390

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000811

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000296

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000284

AC:

AN:

1408370

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

695554

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32218

American (AMR)

AF:

0.0000817

AC:

AN:

36706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25238

East Asian (EAS)

AF:

0.0000273

AC:

AN:

36600

South Asian (SAS)

AF:

0.000288

AC:

AN:

79792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1083716

Other (OTH)

AF:

0.0000171

AC:

AN:

58454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000345

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:2Uncertain:2

Sep 18, 2023

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 367 of the CAPN3 protein (p.Gly367Ser). This variant is present in population databases (rs767106920, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 25079074, 32403337, 33250842; internal data). ClinVar contains an entry for this variant (Variation ID: 468639). 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 expected to disrupt CAPN3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect CAPN3 function (PMID: 17236769). For these reasons, this variant has been classified as Pathogenic. -

Nov 04, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 22, 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. -

not provided

Uncertain:2

Sep 17, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in the single heterozygous state without a second identified CAPN3 variant in a patient with proximal muscle weakness and myopathy, however, this individual was found to be homozygous for a variant in a different gene that may explain the majority of the phenotype (PMID: 33250842); 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: 34201303, 15689361, 32403337, 17236769, 25079074, 16627476, 33250842) -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Mar 27, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Aug 31, 2022

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CAPN3 c.1099G>A (p.Gly367Ser) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. 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 5.5e-05 in 199358 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.5e-05 vs 0.0032), allowing no conclusion about variant significance. c.1099G>A has been reported in the literature as a biallelic genotype in individuals affected with Limb-Girdle Muscular Dystrophy (Saenz_2005, Milic_2007, Nilsson_2014, Gonzalez-Quereda_2020). These data indicate that the variant is likely to be associated with disease. In vitro analysis of muscle biopsy homogenate from a patient demonstrated normal cleavage activity, however the authors suggest that other functional characteristics may be deficient as they only assayed whole tissue homogenates (Milic_2007). Three ClinVar submitters have assessed the variant since 2014 without evidence for independent evaluation: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Pathogenic:1

Mar 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;.;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.8

.;M;.;M

PhyloP100

9.6

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.6

.;D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

.;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.98

MVP

0.99

MPC

0.63

ClinPred

0.84

GERP RS

5.3

Varity_R

0.97

gMVP

0.96

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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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rs767106920

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