Variant 10-95067273-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000371270.6(CYP2C8):c.416G>A(p.Arg139Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,614,040 control chromosomes in the GnomAD database, including 9,726 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.080 ( 613 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9113 hom. )

Consequence

CYP2C8
ENST00000371270.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.144

Variant links:

Genes affected

CYP2C8 (HGNC:2622): (cytochrome P450 family 2 subfamily C member 8) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by phenobarbital. The enzyme is known to metabolize many xenobiotics, including the anticonvulsive drug mephenytoin, benzo(a)pyrene, 7-ethyoxycoumarin, and the anti-cancer drug taxol. This gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

CYP2C8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019239187).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CYP2C8	NM_000770.3 linkuse as main transcript	c.416G>A	p.Arg139Lys	missense_variant	3/9	ENST00000371270.6	NP_000761.3
CYP2C8	NM_001198853.1 linkuse as main transcript	c.206G>A	p.Arg69Lys	missense_variant	3/9		NP_001185782.1
CYP2C8	NM_001198855.1 linkuse as main transcript	c.206G>A	p.Arg69Lys	missense_variant	4/10		NP_001185784.1
CYP2C8	NM_001198854.1 linkuse as main transcript	c.110G>A	p.Arg37Lys	missense_variant	2/8		NP_001185783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6 linkuse as main transcript	c.416G>A	p.Arg139Lys	missense_variant	3/9	1	NM_000770.3	ENSP00000360317	P1	P10632-1

Frequencies

GnomAD3 genomes

AF:

0.0798

AC:

12146

AN:

152124

Hom.:

613

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0211

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.0923

Gnomad ASJ

AF:

0.0914

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0379

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.104

GnomAD3 exomes

AF:

0.0834

AC:

20965

AN:

251460

Hom.:

1122

AF XY:

0.0849

AC XY:

11545

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.0674

Gnomad ASJ exome

AF:

0.0989

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0408

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.106

AC:

154652

AN:

1461798

Hom.:

9113

Cov.:

AF XY:

0.104

AC XY:

75850

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.0186

Gnomad4 AMR exome

AF:

0.0717

Gnomad4 ASJ exome

AF:

0.0956

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0432

Gnomad4 FIN exome

AF:

0.110

Gnomad4 NFE exome

AF:

0.119

Gnomad4 OTH exome

AF:

0.0964

GnomAD4 genome

AF:

0.0798

AC:

12142

AN:

152242

Hom.:

613

Cov.:

AF XY:

0.0792

AC XY:

5892

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0211

Gnomad4 AMR

AF:

0.0922

Gnomad4 ASJ

AF:

0.0914

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0380

Gnomad4 FIN

AF:

0.114

Gnomad4 NFE

AF:

0.114

Gnomad4 OTH

AF:

0.103

Alfa

AF:

0.0876

Hom.:

410

Bravo

AF:

0.0777

TwinsUK

AF:

0.123

AC:

456

ALSPAC

AF:

0.119

AC:

458

ESP6500AA

AF:

0.0245

AC:

108

ESP6500EA

AF:

0.117

AC:

1002

ExAC

AF:

0.0825

AC:

10023

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.120

EpiControl

AF:

0.119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CYP2C8-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.070

.;.;.;T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.34

.;T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;.;.;L;.

MutationTaster

Benign

0.45

P;P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

.;N;.;N;.

REVEL

Benign

0.039

Sift

Benign

0.19

.;T;.;T;.

Sift4G

Benign

0.42

T;T;T;T;T

Polyphen

0.015

.;.;.;B;.

Vest4

0.057

MPC

0.036

ClinPred

0.013

GERP RS

2.8

Varity_R

0.23

gMVP

0.068

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