Variant 2-30743461-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_144575.3(CAPN13):c.1367A>G(p.Tyr456Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,680 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CAPN13
NM_144575.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50

Variant links:

Genes affected

CAPN13 (HGNC:16663): (calpain 13) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes a member of the calpain large subunit family. [provided by RefSeq, Jun 2012]

CAPN13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN13	NM_144575.3 linkuse as main transcript	c.1367A>G	p.Tyr456Cys	missense_variant	13/23	ENST00000295055.12	NP_653176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN13	ENST00000295055.12 linkuse as main transcript	c.1367A>G	p.Tyr456Cys	missense_variant	13/23	5	NM_144575.3	ENSP00000295055	P1	Q6MZZ7-1
CAPN13	ENST00000465450.2 linkuse as main transcript	n.255A>G		non_coding_transcript_exon_variant	3/3	5
CAPN13	ENST00000450650.5 linkuse as main transcript	c.59A>G	p.Tyr20Cys	missense_variant, NMD_transcript_variant	1/11	2		ENSP00000403180
CAPN13	ENST00000458085.6 linkuse as main transcript	c.*51A>G		3_prime_UTR_variant, NMD_transcript_variant	14/16	5		ENSP00000416191		Q6MZZ7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249236

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.1367A>G (p.Y456C) alteration is located in exon 13 (coding exon 12) of the CAPN13 gene. This alteration results from a A to G substitution at nucleotide position 1367, causing the tyrosine (Y) at amino acid position 456 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-8.1

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.92

MutPred

0.80

Loss of phosphorylation at Y456 (P = 0.0318);

MVP

0.96

MPC

0.42

ClinPred

1.0

GERP RS

5.5

Varity_R

0.80

gMVP

0.85

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