10-95058349-T-A

Position:

• chr10-95058349-T-A

Variant summary

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

The NM_000770.3(CYP2C8):​c.805A>T​(p.Ile269Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,613,126 control chromosomes in the GnomAD database, including 1,010 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 0.046 (516 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (494 hom.)
• Consequence: CYP2C8 NM_000770.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.91

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019989312).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C8	NM_000770.3	c.805A>T	p.Ile269Phe	missense_variant	5/9	ENST00000371270.6	NP_000761.3
CYP2C8	NM_001198853.1	c.595A>T	p.Ile199Phe	missense_variant	5/9		NP_001185782.1
CYP2C8	NM_001198855.1	c.595A>T	p.Ile199Phe	missense_variant	6/10		NP_001185784.1
CYP2C8	NM_001198854.1	c.499A>T	p.Ile167Phe	missense_variant	4/8		NP_001185783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6	c.805A>T	p.Ile269Phe	missense_variant	5/9	1	NM_000770.3	ENSP00000360317.3

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 7001 AN: 152100 Hom.: 513 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.0416

GnomAD3 exomes AF: 0.0158 AC: 3975 AN: 251032 Hom.: 208 AF XY: 0.0136 AC XY: 1849 AN XY: 135672

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.00836

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0195

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00998

GnomAD4 exome AF: 0.00759 AC: 11092 AN: 1460908 Hom.: 494 Cov.: 31 AF XY: 0.00753 AC XY: 5472 AN XY: 726760

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.00986

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00196

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0462 AC: 7025 AN: 152218 Hom.: 516 Cov.: 32 AF XY: 0.0450 AC XY: 3352 AN XY: 74432

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00282

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.00633 Hom.: 20

Bravo AF: 0.0527

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.157 AC: 690

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.0194 AC: 2350

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.29
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	.;.;.;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	3.3	.;.;.;M;.
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.9	.;D;.;D;.
REVEL	Benign	0.28
Sift	Uncertain	0.0060	.;D;.;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.96	.;.;.;D;.
Vest4		0.14
MPC		0.18
ClinPred		0.053	T
GERP RS		4.2
Varity_R		0.74
gMVP		0.16

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: rs11572103; hg19: chr10-96818106;