chr15-42409372-G-C

Position:

chr15-42409372-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000070.3(CAPN3):c.1984G>C(p.Ala662Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A662S) has been classified as Pathogenic.

Frequency

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

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.97

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a helix (size 8) in uniprot entity CAN3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000070.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42409372-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3 linkuse as main transcript	c.1984G>C	p.Ala662Pro	missense_variant	17/24	ENST00000397163.8	NP_000061.1	P20807-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.1984G>C	p.Ala662Pro	missense_variant	17/24	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886 linkuse as main transcript	c.-12G>C		5_prime_UTR_variant	4/11			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928 linkuse as main transcript	c.-12G>C		5_prime_UTR_variant	4/11			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146 linkuse as main transcript	c.-12G>C		5_prime_UTR_variant	5/12			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149 linkuse as main transcript	c.-12G>C		5_prime_UTR_variant	4/11			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743 linkuse as main transcript	c.-109G>C		5_prime_UTR_variant	4/11			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 linkuse as main transcript	n.*2420G>C		non_coding_transcript_exon_variant	19/26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 linkuse as main transcript	n.*2420G>C		3_prime_UTR_variant	19/26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251350

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 1442561). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 662 of the CAPN3 protein (p.Ala662Pro). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

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

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.85

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

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

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.2

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

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0, 1.0, 1.0

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

Vest4

0.95

MVP

0.99

MPC

0.70

ClinPred

1.0

GERP RS

5.0

Varity_R

0.96

gMVP

0.87

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