Variant chr1-223627033-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001143962.2(CAPN8):c.685C>T(p.Arg229Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,551,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

CAPN8
NM_001143962.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.481

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27809232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAPN8	NM_001143962.2 linkuse as main transcript	c.685C>T	p.Arg229Trp	missense_variant	5/21	ENST00000366872.10
CAPN8	XM_017001265.2 linkuse as main transcript	c.202C>T	p.Arg68Trp	missense_variant	2/18
CAPN8	XM_017001267.3 linkuse as main transcript	c.685C>T	p.Arg229Trp	missense_variant	5/11
CAPN8	XM_017001268.2 linkuse as main transcript	c.685C>T	p.Arg229Trp	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN8	ENST00000366872.10 linkuse as main transcript	c.685C>T	p.Arg229Trp	missense_variant	5/21	1	NM_001143962.2	P1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000888

AC:

AN:

157732

Hom.:

AF XY:

0.000108

AC XY:

AN XY:

83332

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000445

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:

0.0000489

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000922

AC:

129

AN:

1399684

Hom.:

Cov.:

AF XY:

0.0000884

AC XY:

AN XY:

690334

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000476

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000992

Gnomad4 OTH exome

AF:

0.0000689

GnomAD4 genome

AF:

0.000164

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000147

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

Jul 14, 2022

The c.685C>T (p.R229W) alteration is located in exon 1 (coding exon 1) of the CAPN8 gene. This alteration results from a C to T substitution at nucleotide position 685, causing the arginine (R) at amino acid position 229 to be replaced by a tryptophan (W). 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

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.84

T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0060

D;T;T

Polyphen

1.0

D;.;.

Vest4

0.20

MutPred

0.63

Gain of ubiquitination at K230 (P = 0.0828);Gain of ubiquitination at K230 (P = 0.0828);Gain of ubiquitination at K230 (P = 0.0828);

MVP

0.45

MPC

0.0028

ClinPred

0.32

GERP RS

1.2

Varity_R

0.38

gMVP

0.54

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