rs1057910

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM5BP4_StrongBA1

The NM_000771.4(CYP2C9):c.1075A>C(p.Ile359Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0634 in 1,613,890 control chromosomes in the GnomAD database, including 3,705 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response,other (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I359T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.049 ( 244 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3461 hom. )

Consequence

CYP2C9
NM_000771.4 missense

Scores

Clinical Significance

drug response; other criteria provided, multiple submitters, no conflicts O:10

Conservation

PhyloP100: 0.278

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 -10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-94981297-T-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0023085773).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C9	NM_000771.4 linkuse as main transcript	c.1075A>C	p.Ile359Leu	missense_variant	7/9	ENST00000260682.8	NP_000762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C9	ENST00000260682.8 linkuse as main transcript	c.1075A>C	p.Ile359Leu	missense_variant	7/9	1	NM_000771.4	ENSP00000260682	P1	P11712-1
CYP2C9	ENST00000643112.1 linkuse as main transcript	c.*84A>C		3_prime_UTR_variant, NMD_transcript_variant	6/8			ENSP00000496202

Frequencies

GnomAD3 genomes

AF:

0.0495

AC:

7523

AN:

152122

Hom.:

245

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0491

Gnomad ASJ

AF:

0.0827

Gnomad EAS

AF:

0.0307

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.0558

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0662

Gnomad OTH

AF:

0.0526

GnomAD3 exomes

AF:

0.0631

AC:

15849

AN:

251154

Hom.:

662

AF XY:

0.0682

AC XY:

9258

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.0381

Gnomad ASJ exome

AF:

0.0841

Gnomad EAS exome

AF:

0.0337

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0626

Gnomad NFE exome

AF:

0.0685

Gnomad OTH exome

AF:

0.0630

GnomAD4 exome

AF:

0.0649

AC:

94818

AN:

1461650

Hom.:

3461

Cov.:

AF XY:

0.0662

AC XY:

48127

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0127

Gnomad4 AMR exome

AF:

0.0396

Gnomad4 ASJ exome

AF:

0.0833

Gnomad4 EAS exome

AF:

0.0301

Gnomad4 SAS exome

AF:

0.110

Gnomad4 FIN exome

AF:

0.0627

Gnomad4 NFE exome

AF:

0.0649

Gnomad4 OTH exome

AF:

0.0643

GnomAD4 genome

AF:

0.0494

AC:

7516

AN:

152240

Hom.:

244

Cov.:

AF XY:

0.0499

AC XY:

3715

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0125

Gnomad4 AMR

AF:

0.0490

Gnomad4 ASJ

AF:

0.0827

Gnomad4 EAS

AF:

0.0307

Gnomad4 SAS

AF:

0.114

Gnomad4 FIN

AF:

0.0558

Gnomad4 NFE

AF:

0.0662

Gnomad4 OTH

AF:

0.0511

Alfa

AF:

0.0639

Hom.:

731

Bravo

AF:

0.0462

TwinsUK

AF:

0.0612

AC:

227

ALSPAC

AF:

0.0633

AC:

244

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0659

AC:

567

ExAC

AF:

0.0636

AC:

7727

Asia WGS

AF:

0.0770

AC:

268

AN:

3478

EpiCase

AF:

0.0713

EpiControl

AF:

0.0737

ClinVar

Significance: drug response; other

Submissions summary: Other:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phenytoin response

Other:2

drug response, no assertion criteria provided	literature only	OMIM	Jun 15, 2012	- -
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 No CYP2C9 function

Warfarin response

Other:2

drug response, no assertion criteria provided	literature only	OMIM	Jun 15, 2012	- -
drug response, no assertion criteria provided	research	Pharmacogenomics Lab, Chungbuk National University	Aug 31, 2010	- likely responsive

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

Glipizide response

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Jun 15, 2012

- -

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

not provided

Other:1

other, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 10, 2015

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

Tolbutamide response

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Dec 30, 2010

- -

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

0.15

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.096

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.97

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

REVEL

Benign

0.070

Sift

Uncertain

0.013

Sift4G

Benign

0.36

Polyphen

0.0020

Vest4

0.085

MPC

0.019

ClinPred

0.011

GERP RS

1.1

Varity_R

0.64

gMVP

0.039

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