Variant chr1-223619446-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001143962.2(CAPN8):c.982C>G(p.Leu328Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,399,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

CAPN8
NM_001143962.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.45

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN8	NM_001143962.2 linkuse as main transcript	c.982C>G	p.Leu328Val	missense_variant	9/21	ENST00000366872.10	NP_001137434.1	A6NHC0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN8	ENST00000366872.10 linkuse as main transcript	c.982C>G	p.Leu328Val	missense_variant	9/21	1	NM_001143962.2	ENSP00000355837.6		A6NHC0
CAPN8	ENST00000366873.6 linkuse as main transcript	c.982C>G	p.Leu328Val	missense_variant	9/10	5		ENSP00000355838.2		B1B154

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000648

AC:

AN:

154266

Hom.:

AF XY:

0.00

AC XY:

AN XY:

81864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

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:

0.00000429

AC:

AN:

1399328

Hom.:

Cov.:

AF XY:

0.00000580

AC XY:

AN XY:

690180

show subpopulations

Gnomad4 AFR exome

AF:

0.0000949

Gnomad4 AMR exome

AF:

0.0000280

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:

0.00

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Dec 09, 2023

The c.982C>G (p.L328V) alteration is located in exon 1 (coding exon 1) of the CAPN8 gene. This alteration results from a C to G substitution at nucleotide position 982, causing the leucine (L) at amino acid position 328 to be replaced by a valine (V). 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

Benign

0.074

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.46

T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.0

.;N;N

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.034

B;.;.

Vest4

0.31

MutPred

0.77

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.46

MPC

0.0014

ClinPred

0.61

GERP RS

4.6

Varity_R

0.20

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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