chr10-95067273-C-T

Position:

• chr10-95067273-C-T

Variant summary

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

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
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.144

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=0.0019239187).
• 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	UniProt
CYP2C8	NM_000770.3	c.416G>A	p.Arg139Lys	missense_variant	3/9	ENST00000371270.6	NP_000761.3
CYP2C8	NM_001198853.1	c.206G>A	p.Arg69Lys	missense_variant	3/9		NP_001185782.1
CYP2C8	NM_001198855.1	c.206G>A	p.Arg69Lys	missense_variant	4/10		NP_001185784.1
CYP2C8	NM_001198854.1	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	c.416G>A	p.Arg139Lys	missense_variant	3/9	1	NM_000770.3	ENSP00000360317	P1

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12146 AN: 152124 Hom.: 613 Cov.: 32

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

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.: 33 AF XY: 0.104 AC XY: 75850 AN XY: 727204

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.: 32 AF XY: 0.0792 AC XY: 5892 AN XY: 74430

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: 54 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

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	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	.;.;.;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.34	.;T;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;.;.;L;.
MutationTaster	Benign	0.45	P;P;P
PrimateAI	Benign	0.36	T
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	T
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

Other links and lift over

dbSNP: rs11572080; hg19: chr10-96827030; COSMIC: COSV64875934;