10-95058362-G-C

Position:

chr10-95058362-G-C

Variant summary

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

The NM_000770.3(CYP2C8):c.792C>G(p.Ile264Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,613,150 control chromosomes in the GnomAD database, including 1,876 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.035 ( 120 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1756 hom. )

Consequence

CYP2C8
NM_000770.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: -0.579

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:

CYP2C8 (HGNC:):

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=0.0040852427).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C8	NM_000770.3 linkuse as main transcript	c.792C>G	p.Ile264Met	missense_variant	5/9	ENST00000371270.6	NP_000761.3	P10632-1
CYP2C8	NM_001198853.1 linkuse as main transcript	c.582C>G	p.Ile194Met	missense_variant	5/9		NP_001185782.1	P10632B7Z1F5
CYP2C8	NM_001198855.1 linkuse as main transcript	c.582C>G	p.Ile194Met	missense_variant	6/10		NP_001185784.1	P10632B7Z1F5
CYP2C8	NM_001198854.1 linkuse as main transcript	c.486C>G	p.Ile162Met	missense_variant	4/8		NP_001185783.1	P10632-2B7Z1F5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6 linkuse as main transcript	c.792C>G	p.Ile264Met	missense_variant	5/9	1	NM_000770.3	ENSP00000360317.3		P10632-1

Frequencies

GnomAD3 genomes

AF:

0.0355

AC:

5397

AN:

152042

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0312

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.0582

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0521

Gnomad OTH

AF:

0.0368

GnomAD3 exomes

AF:

0.0375

AC:

9410

AN:

251022

Hom.:

217

AF XY:

0.0374

AC XY:

5069

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.0274

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0146

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0543

Gnomad OTH exome

AF:

0.0427

GnomAD4 exome

AF:

0.0463

AC:

67688

AN:

1460990

Hom.:

1756

Cov.:

AF XY:

0.0456

AC XY:

33142

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.00951

Gnomad4 AMR exome

AF:

0.0278

Gnomad4 ASJ exome

AF:

0.0201

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0151

Gnomad4 FIN exome

AF:

0.0599

Gnomad4 NFE exome

AF:

0.0526

Gnomad4 OTH exome

AF:

0.0419

GnomAD4 genome

AF:

0.0354

AC:

5394

AN:

152160

Hom.:

120

Cov.:

AF XY:

0.0345

AC XY:

2568

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0119

Gnomad4 AMR

AF:

0.0310

Gnomad4 ASJ

AF:

0.0185

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0150

Gnomad4 FIN

AF:

0.0582

Gnomad4 NFE

AF:

0.0521

Gnomad4 OTH

AF:

0.0365

Alfa

AF:

0.0400

Hom.:

106

Bravo

AF:

0.0332

TwinsUK

AF:

0.0491

AC:

182

ALSPAC

AF:

0.0483

AC:

186

ESP6500AA

AF:

0.0129

AC:

ESP6500EA

AF:

0.0548

AC:

471

ExAC

AF:

0.0386

AC:

4687

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0480

EpiControl

AF:

0.0527

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CYP2C8-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2020

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). -

CYP2C8 POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jun 20, 2018

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.23

CADD

Benign

4.8

DANN

Benign

0.96

DEOGEN2

Benign

0.27

.;.;.;T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.86

.;D;D;D;D

MetaRNN

Benign

0.0041

T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Pathogenic

3.0

.;.;.;M;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

.;D;.;D;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0030

.;D;.;D;.

Sift4G

Uncertain

0.016

D;D;D;D;D

Polyphen

0.99

.;.;.;D;.

Vest4

0.29

MPC

0.18

ClinPred

0.094

GERP RS

-2.8

Varity_R

0.89

gMVP

0.21

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