10-95058362-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.579

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]

ACMG classification

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	UniProt
CYP2C8	NM_000770.3	c.792C>G	p.Ile264Met	missense_variant	5/9	ENST00000371270.6
CYP2C8	NM_001198853.1	c.582C>G	p.Ile194Met	missense_variant	5/9
CYP2C8	NM_001198855.1	c.582C>G	p.Ile194Met	missense_variant	6/10
CYP2C8	NM_001198854.1	c.486C>G	p.Ile162Met	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C8	ENST00000371270.6	c.792C>G	p.Ile264Met	missense_variant	5/9	1	NM_000770.3	P1

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5397 AN: 152042 Hom.: 120 Cov.: 32

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

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.: 31 AF XY: 0.0456 AC XY: 33142 AN XY: 726798

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.: 32 AF XY: 0.0345 AC XY: 2568 AN XY: 74400

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: 57

ESP6500EA AF: 0.0548 AC: 471

ExAC AF: 0.0386 AC: 4687

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0480

EpiControl AF: 0.0527

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

CYP2C8-related disorder Benign:1

Benign, criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	4.8
Dann	Benign	0.96
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.49	N
MetaRNN	Benign	0.0041	T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	0.54	D;D;N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.99	.;.;.;D;.
Vest4		0.29
MPC		0.18
ClinPred		0.094	T
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

Other links and lift over

dbSNP: rs1058930; hg19: chr10-96818119; COSMIC: COSV64877126;