10-94942290-C-T

Variant summary

Our verdict is Benign. Variant got -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 same amino acid change has been previously reported as Likely benignin 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:6

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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE	UniProt
CYP2C9	NM_000771.4 linkuse as main transcript	c.430C>T	p.Arg144Cys	missense_variant	3/9	ENST00000260682.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C9	ENST00000260682.8 linkuse as main transcript	c.430C>T	p.Arg144Cys	missense_variant	3/9	1	NM_000771.4	P1	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

GnomAD3 exomes

AF:

0.0920

AC:

23117

AN:

251228

Hom.:

1356

AF XY:

0.0940

AC XY:

12761

AN XY:

135766

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 SAS exome

AF:

0.0467

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

Gnomad4 AMR exome

AF:

0.0722

Gnomad4 ASJ exome

AF:

0.138

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0490

Gnomad4 FIN exome

AF:

0.113

Gnomad4 NFE exome

AF:

0.132

Gnomad4 OTH exome

AF:

0.106

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

Gnomad4 AMR

AF:

0.0978

Gnomad4 ASJ

AF:

0.135

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0388

Gnomad4 FIN

AF:

0.118

Gnomad4 NFE

AF:

0.127

Gnomad4 OTH

AF:

0.110

Alfa

AF:

0.108

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2018

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

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Feb 11, 2019

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

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Feb 11, 2019

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

drug response, no assertion criteria provided

case-control

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Sep 24, 2020

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

Warfarin response

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Aug 09, 2018

- -

not provided

Other:1

other, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 09, 2015

- 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

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Feb 11, 2019

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

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

MutationTaster

Benign

0.0018

PrimateAI

Benign

0.35

Polyphen

1.0

.;D

Vest4

0.15

MPC

0.051

ClinPred

0.072

GERP RS

1.4

Varity_R

0.65

gMVP

0.20

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