Variant 1-223616136-C-G 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_001143962.2(CAPN8):c.1145G>C(p.Trp382Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000502 in 1,394,278 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: 33)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

CAPN8
NM_001143962.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.99

Variant links:

Genes affected

CAPN8 (HGNC:1485): (calpain 8) Predicted to enable calcium-dependent cysteine-type endopeptidase activity and identical protein binding activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within calcium-dependent self proteolysis. Predicted to be located in Golgi apparatus. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CAPN8 links:

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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, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN8	NM_001143962.2 linkuse as main transcript	c.1145G>C	p.Trp382Ser	missense_variant	10/21	ENST00000366872.10	NP_001137434.1	A6NHC0
CAPN8	XM_017001265.2 linkuse as main transcript	c.662G>C	p.Trp221Ser	missense_variant	7/18		XP_016856754.1
CAPN8	XM_017001266.2 linkuse as main transcript	c.464G>C	p.Trp155Ser	missense_variant	5/16		XP_016856755.1
CAPN8	XM_017001267.3 linkuse as main transcript	c.1311G>C	p.Leu437Leu	synonymous_variant	11/11		XP_016856756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN8	ENST00000366872.10 linkuse as main transcript	c.1145G>C	p.Trp382Ser	missense_variant	10/21	1	NM_001143962.2	ENSP00000355837.6		A6NHC0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000386

AC:

AN:

155540

Hom.:

AF XY:

0.0000608

AC XY:

AN XY:

82240

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000244

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:

0.00

GnomAD4 exome

AF:

0.00000502

AC:

AN:

1394278

Hom.:

Cov.:

AF XY:

0.00000583

AC XY:

AN XY:

686396

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000168

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:

9.30e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

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

Sep 17, 2021

The c.1145G>C (p.W382S) alteration is located in exon 1 (coding exon 1) of the CAPN8 gene. This alteration results from a G to C substitution at nucleotide position 1145, causing the tryptophan (W) at amino acid position 382 to be replaced by a serine (S). 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

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-12

.;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

.;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

D;.

Vest4

0.67

MutPred

0.86

Gain of disorder (P = 0.0158);Gain of disorder (P = 0.0158);

MVP

0.66

MPC

0.0017

ClinPred

0.98

GERP RS

5.2

Varity_R

0.39

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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