rs886042557

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000070.3(CAPN3):c.2105C>T(p.Ala702Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,459,604 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. A702E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.05

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 2 (size 33) in uniprot entity CAN3_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_000070.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42409985-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 15-42409985-C-T is Pathogenic according to our data. Variant chr15-42409985-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 283099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42409985-C-T is described in Lovd as [Pathogenic]. Variant chr15-42409985-C-T is described in Lovd as [Pathogenic]. Variant chr15-42409985-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-42409985-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2105C>T	p.Ala702Val	missense_variant	Exon 19 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.2105C>T	p.Ala702Val	missense_variant	Exon 19 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.110C>T	p.Ala37Val	missense_variant	Exon 6 of 11			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.110C>T	p.Ala37Val	missense_variant	Exon 6 of 11			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.110C>T	p.Ala37Val	missense_variant	Exon 7 of 12			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.110C>T	p.Ala37Val	missense_variant	Exon 6 of 11			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.8C>T	p.Ala3Val	missense_variant	Exon 6 of 11			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2541C>T		non_coding_transcript_exon_variant	Exon 21 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*2541C>T		3_prime_UTR_variant	Exon 21 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251260

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135788

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:

0.00000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459604

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726132

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:

0.0000187

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:3

Sep 13, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 702 of the CAPN3 protein (p.Ala702Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 16141003, 17236769, 27234031, 27262448, 30056071). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 283099). 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. -

Sep 27, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000283099 /PMID: 9150160). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 17236769, 27262448). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Mar 24, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); 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: 30056071, 27234031, 10330340, 9150160, 19556129, 16411092, 16650086, 15757244, 9266733, 27262448, 17994539, 17236769, 16141003, 35741838) -

Sep 15, 2015

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Feb 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

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

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

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

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.96

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

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.5

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

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.3

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

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.023

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

Polyphen

1.0

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

Vest4

0.95

MutPred

0.85

.;.;.;Loss of disorder (P = 0.1191);.;.;.;.;.;.;.;.;

MVP

0.96

MPC

0.63

ClinPred

0.94

GERP RS

4.9

Varity_R

0.70

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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