chr10-94942290-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000771.4(CYP2C9):c.430C>T(p.Arg144Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,772 control chromosomes in the GnomAD database, including 11,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,drug response,other (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.088 ( 755 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11216 hom. )

Consequence

CYP2C9
NM_000771.4 missense

Scores

Clinical Significance

Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:1O:7

Conservation

PhyloP100: -0.0520

Variant links:

Genes affected

CYP2C9 (HGNC:2623): (cytochrome P450 family 2 subfamily C member 9) 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 rifampin. The enzyme is known to metabolize many xenobiotics, including phenytoin, tolbutamide, ibuprofen and S-warfarin. Studies identifying individuals who are poor metabolizers of phenytoin and tolbutamide suggest that this gene is polymorphic. The gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. [provided by RefSeq, Jul 2008]

CYP2C9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008835256).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C9	NM_000771.4 link	c.430C>T	p.Arg144Cys	missense_variant	Exon 3 of 9	ENST00000260682.8	NP_000762.2	P11712-1S5RV20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C9	ENST00000260682.8 link	c.430C>T	p.Arg144Cys	missense_variant	Exon 3 of 9	1	NM_000771.4	ENSP00000260682.6		P11712-1

Frequencies

GnomAD3 genomes

AF:

0.0882

AC:

13405

AN:

152046

Hom.:

755

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0236

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.0980

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0388

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.112

GnomAD2 exomes

AF:

0.0920

AC:

23117

AN:

251228

AF XY:

0.0940

show subpopulations

Gnomad AFR exome

AF:

0.0223

Gnomad AMR exome

AF:

0.0680

Gnomad ASJ exome

AF:

0.136

Gnomad EAS exome

AF:

0.000436

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.128

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.118

AC:

171842

AN:

1461608

Hom.:

11216

Cov.:

AF XY:

0.116

AC XY:

84405

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0195

AC:

652

AN:

33460

Gnomad4 AMR exome

AF:

0.0722

AC:

3227

AN:

44696

Gnomad4 ASJ exome

AF:

0.138

AC:

3599

AN:

26124

Gnomad4 EAS exome

AF:

0.000227

AC:

AN:

39688

Gnomad4 SAS exome

AF:

0.0490

AC:

4230

AN:

86254

Gnomad4 FIN exome

AF:

0.113

AC:

6063

AN:

53420

Gnomad4 NFE exome

AF:

0.132

AC:

146976

AN:

1111836

Gnomad4 Remaining exome

AF:

0.106

AC:

6393

AN:

60366

Heterozygous variant carriers

9812

19625

29437

39250

49062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

5244

10488

15732

20976

26220

<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:

0.0881

AC:

13400

AN:

152164

Hom.:

755

Cov.:

AF XY:

0.0870

AC XY:

6471

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0235

AC:

0.0235218

AN:

0.0235218

Gnomad4 AMR

AF:

0.0978

AC:

0.097799

AN:

0.097799

Gnomad4 ASJ

AF:

0.135

AC:

0.135369

AN:

0.135369

Gnomad4 EAS

AF:

0.000387

AC:

0.000386847

AN:

0.000386847

Gnomad4 SAS

AF:

0.0388

AC:

0.0387967

AN:

0.0387967

Gnomad4 FIN

AF:

0.118

AC:

0.117986

AN:

0.117986

Gnomad4 NFE

AF:

0.127

AC:

0.126607

AN:

0.126607

Gnomad4 OTH

AF:

0.110

AC:

0.110427

AN:

0.110427

Heterozygous variant carriers

609

1218

1827

2436

3045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.102

Hom.:

499

Bravo

AF:

0.0859

TwinsUK

AF:

0.136

AC:

503

ALSPAC

AF:

0.134

AC:

515

ESP6500AA

AF:

0.0268

AC:

118

ESP6500EA

AF:

0.131

AC:

1124

ExAC

AF:

0.0914

AC:

11093

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.132

EpiControl

AF:

0.131

ClinVar

Significance: Likely benign; drug response; other

Submissions summary: Benign:1Other:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Warfarin response

Other:2

Aug 09, 2018

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Faculty of Pharmacy, Damascus University

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

rs1799853 is a SNP in the CYP2C9 gene and is linked to poor warfarin metabolism and risk of GI bleeding with warfarin, rs1799853 is associated with reduced enzyme activity and lower clearance rates of warfarin leading to higher rates of warfarin concentration likely responsive

not specified

Benign:1

Mar 09, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Piroxicam response

Other:1

Feb 11, 2019

Medical Genetics Summaries

Significance:drug response

Review Status:criteria provided, single submitter

Collection Method:curation

Individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) have reduced clearance of piroxicam. Because the standard recommended dose of piroxicam may cause abnormally high plasma levels, a dose reduction should be considered for these individuals. Poor metabolizer

Lesinurad response

Other:1

Feb 11, 2019

Medical Genetics Summaries

Significance:drug response

Review Status:criteria provided, single submitter

Collection Method:curation

Lesinurad should be used with caution in individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) because of increased exposure and an increased risk of side effects. Poor metabolizer

Phenytoin response

Other:1

Sep 24, 2020

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:case-control

May cause toxicity/ADR and poor metabolism/PK Decreased CYP2C9 function

not provided

Other:1

Jul 09, 2015

Eurofins Ntd Llc (ga)

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Flurbiprofen response

Other:1

Feb 11, 2019

Medical Genetics Summaries

Significance:drug response

Review Status:criteria provided, single submitter

Collection Method:curation

The dose of flurbiprofen should be reduced in individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) to avoid abnormally high plasma levels due to reduced metabolic clearance. Poor metabolizer

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T

Eigen

Benign

-0.080

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-6.5

.;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.028

.;D

Sift4G

Uncertain

0.019

.;D

Polyphen

1.0

.;D

Vest4

0.15

MPC

0.051

ClinPred

0.072

GERP RS

1.4

Varity_R

0.65

gMVP

0.20

Mutation Taster

=89/11

polymorphism (auto)

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over