rs774048743

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong

The NM_000070.3(CAPN3):c.133G>A(p.Ala45Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,614,066 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. A45V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 8.35

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.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42359939-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2199528.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

PP5

Variant 15-42359938-G-A is Pathogenic according to our data. Variant chr15-42359938-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42359938-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAPN3	NM_000070.3 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	1/24	ENST00000397163.8
CAPN3	NM_024344.2 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	1/23
CAPN3	NM_173087.2 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	1/24	1	NM_000070.3	P2	P20807-1
CAPN3	ENST00000357568.8 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	1/23	1			P20807-3
CAPN3	ENST00000349748.8 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	1/21	1			P20807-2
CAPN3	ENST00000318023.11 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	1/23	5		A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251398

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000791

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 45 of the CAPN3 protein (p.Ala45Thr). This variant is present in population databases (rs774048743, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15351423, 16650086, 18055493, 19556129). ClinVar contains an entry for this variant (Variation ID: 217148). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 04, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 03, 2023

- -

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

May 08, 2023

Variant summary: CAPN3 c.133G>A (p.Ala45Thr) results in a non-conservative amino acid change in 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 1.2e-05 in 251398 control chromosomes (gnomAD). c.133G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Chrobakova_2004, Groen_2007). These data indicate that the variant is very likely to be associated with disease. 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: 15351423, 18055493). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=2)/likely pathogenic (n=2). 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

Oct 31, 2018

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.32

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.030

T;.;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

0.31

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.72

N;N;N;N

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0070

D;D;D;D

Sift4G

Benign

0.20

T;T;T;T

Polyphen

1.0

.;D;D;D

Vest4

0.89

MutPred

0.73

Gain of glycosylation at S44 (P = 0.1063);Gain of glycosylation at S44 (P = 0.1063);Gain of glycosylation at S44 (P = 0.1063);Gain of glycosylation at S44 (P = 0.1063);

MVP

0.95

MPC

0.62

ClinPred

0.94

GERP RS

6.0

Varity_R

0.20

gMVP

0.82

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