10-95038992-T-C

Variant summary

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

The NM_000770.3(CYP2C8):c.1196A>G(p.Lys399Arg) 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 1,613,204 control chromosomes in the GnomAD database, including 9,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.080 (610 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9109 hom.)
• Consequence: CYP2C8 NM_000770.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.323

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=0.0021723509).
• 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	UniProt
CYP2C8	NM_000770.3	c.1196A>G	p.Lys399Arg	missense_variant	8/9	ENST00000371270.6
CYP2C8	NM_001198853.1	c.986A>G	p.Lys329Arg	missense_variant	8/9
CYP2C8	NM_001198855.1	c.986A>G	p.Lys329Arg	missense_variant	9/10
CYP2C8	NM_001198854.1	c.890A>G	p.Lys297Arg	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C8	ENST00000371270.6	c.1196A>G	p.Lys399Arg	missense_variant	8/9	1	NM_000770.3	P1

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12149 AN: 152168 Hom.: 610 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0924

Gnomad ASJ AF: 0.0913

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.0834 AC: 20976 AN: 251410 Hom.: 1121 AF XY: 0.0850 AC XY: 11545 AN XY: 135876

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.0675

Gnomad ASJ exome AF: 0.0990

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: 154417 AN: 1460918 Hom.: 9109 Cov.: 30 AF XY: 0.104 AC XY: 75770 AN XY: 726856

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.0717

Gnomad4 ASJ exome AF: 0.0956

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0432

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.0963

GnomAD4 genome AF: 0.0798 AC: 12145 AN: 152286 Hom.: 610 Cov.: 32 AF XY: 0.0791 AC XY: 5892 AN XY: 74456

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.0923

Gnomad4 ASJ AF: 0.0913

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0378

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.104

Alfa AF: 0.107 Hom.: 2541

Bravo AF: 0.0778

TwinsUK AF: 0.123 AC: 456

ALSPAC AF: 0.119 AC: 459

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.117 AC: 1003

ExAC AF: 0.0826 AC: 10028

Asia WGS AF: 0.0150 AC: 55 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

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

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). -

Pulmonary disease, chronic obstructive, susceptibility to Other:1

association, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Jul 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.4
Dann	Benign	0.95
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.045	N
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.021	.;.;.;B
Vest4		0.095
MPC		0.021
ClinPred		0.014	T
GERP RS		-1.4
Varity_R		0.23
gMVP		0.041

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10509681; hg19: chr10-96798749; COSMIC: COSV64875925; COSMIC: COSV64875925;