15-42410633-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000070.3(CAPN3):c.2230A>G(p.Ser744Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,838 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 4.26

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:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 15-42410633-A-G is Pathogenic according to our data. Variant chr15-42410633-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 555001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42410633-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2230A>G	p.Ser744Gly	missense_variant	Exon 21 of 24	ENST00000397163.8	NP_000061.1	P20807-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.2230A>G	p.Ser744Gly	missense_variant	Exon 21 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.235A>G	p.Ser79Gly	missense_variant	Exon 8 of 11			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.235A>G	p.Ser79Gly	missense_variant	Exon 8 of 11			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.235A>G	p.Ser79Gly	missense_variant	Exon 9 of 12			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.235A>G	p.Ser79Gly	missense_variant	Exon 8 of 11			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.133A>G	p.Ser45Gly	missense_variant	Exon 8 of 11			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2666A>G		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*2666A>G		3_prime_UTR_variant	Exon 23 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251302

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135832

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727218

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	Consanguinity: No Clinical Indications: Difficulty climbing stairs and lifting objects since 5 years, waddling gait, Power- weak biceps, weak lower limb adduction Investigations: CPK - 1487 U/L Family history: Sister is similarly affected Clinical Suspicion: Limb Girdle Muscular Dystrophy -
Uncertain significance, flagged submission	clinical testing	Counsyl	Nov 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 04, 2021	This variant has been observed to segregate with limb-girdle muscular dystrophy in several families (PMID: 7720071, 8624690, 9655129). ClinVar contains an entry for this variant (Variation ID: 555001). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change causes constitutive autolysis¬†(PMID: 9642272). This variant is present in population databases (rs750083132, ExAC 0.002%). This sequence change replaces serine with glycine at codon 744 of the CAPN3 protein (p.Ser744Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Baylor Genetics

Sep 06, 2022

- -

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

Aug 10, 2023

Variant summary: CAPN3 c.2230A>G (p.Ser744Gly) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) 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 8e-06 in 251302 control chromosomes. c.2230A>G has been reported in the literature in at-least three individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive as being a compound heterozygous state along with two different pathogenic variants, respectively (examples: Anderson_1998, Ono_1998, Penisson-Besnier_1998, Richard_1995). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in completely loss of proteolysis activity against the substrate fodrin (Richard_1995). Additionally, significantly decreased CAPN3 levels in muscular biopsy, determined by Western blotting, have been found in at-least two patients carrying c.2230A>G and second null alleles, respectively (Anderson_1998). These data indicate that the variant is very likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9777948, 9642272, 9655129, 7720071). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic n=2; VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

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

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

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

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.95

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

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.3

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

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.3

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

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

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

Sift4G

Benign

0.14

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

Polyphen

1.0, 1.0

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

Vest4

0.91

MutPred

0.87

.;.;.;Loss of disorder (P = 0.1102);.;.;.;.;.;.;.;.;

MVP

0.87

MPC

0.60

ClinPred

0.98

GERP RS

4.5

Varity_R

0.77

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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