10-94942309-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000771.4(CYP2C9):c.449G>A(p.Arg150His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,613,840 control chromosomes in the GnomAD database, including 155 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 Likely benign,drug response (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.016 ( 81 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 74 hom. )

Consequence

CYP2C9
NM_000771.4 missense

Scores

Clinical Significance

Benign/Likely benign; drug response criteria provided, multiple submitters, no conflicts B:2O:3

Conservation

PhyloP100: -0.771

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=0.0048422813).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0531 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.449G>A	p.Arg150His	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.449G>A	p.Arg150His	missense_variant	3/9	1	NM_000771.4	P1	P11712-1

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2405

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0549

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00862

GnomAD3 exomes

AF:

0.00440

AC:

1106

AN:

251202

Hom.:

AF XY:

0.00328

AC XY:

445

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.0589

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00199

AC:

2913

AN:

1461596

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1244

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0594

Gnomad4 AMR exome

AF:

0.00217

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000568

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000438

Gnomad4 OTH exome

AF:

0.00446

GnomAD4 genome

AF:

0.0159

AC:

2415

AN:

152244

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1146

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0550

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00853

Alfa

AF:

0.00511

Hom.:

Bravo

AF:

0.0179

ESP6500AA

AF:

0.0581

AC:

256

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00524

AC:

636

EpiCase

AF:

0.000763

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign; drug response

Submissions summary: Benign:2Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 25087612, 24118918, 22378156, 23376925, 23752738, 25142737, 25832633) -

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

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

0.080

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.50

Cadd

Benign

5.7

Dann

Benign

0.84

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.032

T;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.20

Polyphen

0.016

.;B

Vest4

0.12

MVP

0.58

MPC

0.0086

ClinPred

0.0040

GERP RS

-4.3

Varity_R

0.081

gMVP

0.080

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