rs41286886

Positions:

• chr10-95064901-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000770.3(CYP2C8):​c.541G>A​(p.Val181Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,613,260 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (44 hom.)
• Consequence: CYP2C8 NM_000770.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.860

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0097284615).
• BP6: Variant 10-95064901-C-T is Benign according to our data. Variant chr10-95064901-C-T is described in ClinVar as [Benign]. Clinvar id is 787628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C8	NM_000770.3	c.541G>A	p.Val181Ile	missense_variant	4/9	ENST00000371270.6
CYP2C8	NM_001198853.1	c.331G>A	p.Val111Ile	missense_variant	4/9
CYP2C8	NM_001198855.1	c.331G>A	p.Val111Ile	missense_variant	5/10
CYP2C8	NM_001198854.1	c.235G>A	p.Val79Ile	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C8	ENST00000371270.6	c.541G>A	p.Val181Ile	missense_variant	4/9	1	NM_000770.3	P1

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 757 AN: 151862 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00675

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00827

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00485 AC: 1220 AN: 251290 Hom.: 7 AF XY: 0.00477 AC XY: 648 AN XY: 135808

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00744

Gnomad NFE exome AF: 0.00815

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00701 AC: 10237 AN: 1461280 Hom.: 44 Cov.: 31 AF XY: 0.00682 AC XY: 4958 AN XY: 726946

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.00685

Gnomad4 NFE exome AF: 0.00845

Gnomad4 OTH exome AF: 0.00494

GnomAD4 genome AF: 0.00498 AC: 757 AN: 151980 Hom.: 4 Cov.: 32 AF XY: 0.00452 AC XY: 336 AN XY: 74264

Gnomad4 AFR AF: 0.00138

Gnomad4 AMR AF: 0.00400

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00675

Gnomad4 NFE AF: 0.00827

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00719 Hom.: 6

Bravo AF: 0.00456

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00485 AC: 589

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00581

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2018	- -

CYP2C8-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.8
DANN	Benign	0.37
DEOGEN2	Benign	0.037	.;.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.68	.;T;T;T;T
MetaRNN	Benign	0.0097	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.2	.;.;.;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.35	.;N;.;N;.
REVEL	Benign	0.050
Sift	Benign	1.0	.;T;.;T;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0040	.;.;.;B;.
Vest4		0.12
MVP		0.31
MPC		0.020
ClinPred		0.00047	T
GERP RS		0.35
Varity_R		0.046
gMVP		0.033

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41286886; hg19: chr10-96824658; COSMIC: COSV64877820;