10-95038992-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,association (no stars).

Frequency

Genomes: 𝑓 0.080 ( 610 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9109 hom. )

Consequence

CYP2C8
NM_000770.3 missense

Scores

Clinical Significance

Benign; association no assertion criteria provided B:1O:1

Conservation

PhyloP100: 0.323

Publications

224 publications found

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021723509).

BP6

Variant 10-95038992-T-C is Benign according to our data. Variant chr10-95038992-T-C is described in ClinVar as [Benign, association]. Clinvar id is 375654.Status of the report is no_assertion_criteria_provided, 0 stars.

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 rank	MANE	Protein	UniProt
CYP2C8	NM_000770.3 link	c.1196A>G	p.Lys399Arg	missense_variant	Exon 8 of 9	ENST00000371270.6	NP_000761.3	P10632-1
CYP2C8	NM_001198853.1 link	c.986A>G	p.Lys329Arg	missense_variant	Exon 8 of 9		NP_001185782.1	P10632B7Z1F5
CYP2C8	NM_001198855.1 link	c.986A>G	p.Lys329Arg	missense_variant	Exon 9 of 10		NP_001185784.1	P10632B7Z1F5
CYP2C8	NM_001198854.1 link	c.890A>G	p.Lys297Arg	missense_variant	Exon 7 of 8		NP_001185783.1	P10632-2B7Z1F5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6 link	c.1196A>G	p.Lys399Arg	missense_variant	Exon 8 of 9	1	NM_000770.3	ENSP00000360317.3		P10632-1

Frequencies

GnomAD3 genomes

AF:

0.0798

AC:

12149

AN:

152168

Hom.:

610

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0834

AC:

20976

AN:

251410

AF XY:

0.0850

show subpopulations

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 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.:

AF XY:

0.104

AC XY:

75770

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.0185

AC:

620

AN:

33472

American (AMR)

AF:

0.0717

AC:

3207

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0956

AC:

2498

AN:

26126

East Asian (EAS)

AF:

0.000151

AC:

AN:

39692

South Asian (SAS)

AF:

0.0432

AC:

3724

AN:

86244

European-Finnish (FIN)

AF:

0.110

AC:

5861

AN:

53412

Middle Eastern (MID)

AF:

0.121

AC:

697

AN:

5768

European-Non Finnish (NFE)

AF:

0.119

AC:

131989

AN:

1111108

Other (OTH)

AF:

0.0963

AC:

5815

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

6633

13266

19899

26532

33165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0798

AC:

12145

AN:

152286

Hom.:

610

Cov.:

AF XY:

0.0791

AC XY:

5892

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0211

AC:

878

AN:

41572

American (AMR)

AF:

0.0923

AC:

1411

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0913

AC:

317

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5192

South Asian (SAS)

AF:

0.0378

AC:

182

AN:

4820

European-Finnish (FIN)

AF:

0.113

AC:

1199

AN:

10596

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7751

AN:

68018

Other (OTH)

AF:

0.104

AC:

220

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

584

1168

1751

2335

2919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.103

Hom.:

4436

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:

AN:

3478

EpiCase

AF:

0.120

EpiControl

AF:

0.119

ClinVar

Significance: Benign; association

Submissions summary: Benign:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CYP2C8-related disorder

Benign:1

Oct 29, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jul 05, 2022

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance:association

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.4

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.25

.;.;.;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.73

.;T;T;T

MetaRNN

Benign

0.0022

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

.;.;.;M

PhyloP100

0.32

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.3

.;N;.;N

REVEL

Benign

0.054

Sift

Benign

0.046

.;D;.;T

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.021

.;.;.;B

Vest4

0.095

MPC

0.021

ClinPred

0.014

GERP RS

-1.4

Varity_R

0.23

gMVP

0.041

Mutation Taster

=83/17

polymorphism (auto)

(source)

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

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10-95038992-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over