rs41286886

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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. 16/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.860

Publications

14 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 -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 VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000770.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP2C8	NM_000770.3	MANE Select	c.541G>A	p.Val181Ile	missense	Exon 4 of 9	NP_000761.3
CYP2C8	NM_001198853.1		c.331G>A	p.Val111Ile	missense	Exon 4 of 9	NP_001185782.1
CYP2C8	NM_001198855.1		c.331G>A	p.Val111Ile	missense	Exon 5 of 10	NP_001185784.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP2C8	ENST00000371270.6	TSL:1 MANE Select	c.541G>A	p.Val181Ile	missense	Exon 4 of 9	ENSP00000360317.3
CYP2C8	ENST00000854622.1		c.541G>A	p.Val181Ile	missense	Exon 4 of 10	ENSP00000524681.1
CYP2C8	ENST00000854631.1		c.541G>A	p.Val181Ile	missense	Exon 4 of 10	ENSP00000524690.1

Frequencies

GnomAD3 genomes

AF:

0.00498

AC:

757

AN:

151862

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00485

AC:

1220

AN:

251290

AF XY:

0.00477

show subpopulations

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 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.:

Cov.:

AF XY:

0.00682

AC XY:

4958

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33466

American (AMR)

AF:

0.00161

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39678

South Asian (SAS)

AF:

0.000673

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00685

AC:

366

AN:

53416

Middle Eastern (MID)

AF:

0.000372

AC:

AN:

5378

European-Non Finnish (NFE)

AF:

0.00845

AC:

9397

AN:

1111942

Other (OTH)

AF:

0.00494

AC:

298

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

548

1096

1643

2191

2739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00498

AC:

757

AN:

151980

Hom.:

Cov.:

AF XY:

0.00452

AC XY:

336

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.00138

AC:

AN:

41446

American (AMR)

AF:

0.00400

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000416

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00675

AC:

AN:

10524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00827

AC:

562

AN:

67980

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

107

143

179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00445

Hom.:

Bravo

AF:

0.00456

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00485

AC:

589

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00581

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CYP2C8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.8

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.037

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0097

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.2

PhyloP100

-0.86

PrimateAI

Benign

0.30

PROVEAN

Benign

0.35

REVEL

Benign

0.050

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0040

Vest4

0.12

MVP

0.31

MPC

0.020

ClinPred

0.00047

GERP RS

0.35

Varity_R

0.046

gMVP

0.033

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over