10-94981224-C-T

Position:

chr10-94981224-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000771.4(CYP2C9):c.1003C>T(p.Arg335Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,613,852 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts 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 0.0070 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 17 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: 1.19

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=0.008629888).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00701 (1067/152210) while in subpopulation AFR AF= 0.0174 (721/41552). AF 95% confidence interval is 0.0163. There are 7 homozygotes in gnomad4. There are 503 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1067 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C9	NM_000771.4 linkuse as main transcript	c.1003C>T	p.Arg335Trp	missense_variant	7/9	ENST00000260682.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C9	ENST00000260682.8 linkuse as main transcript	c.1003C>T	p.Arg335Trp	missense_variant	7/9	1	NM_000771.4	P1	P11712-1
CYP2C9	ENST00000643112.1 linkuse as main transcript	c.*12C>T		3_prime_UTR_variant, NMD_transcript_variant	6/8

Frequencies

GnomAD3 genomes

AF:

0.00702

AC:

1067

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00642

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00285

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00359

AC:

901

AN:

251132

Hom.:

AF XY:

0.00337

AC XY:

458

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.0204

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00248

Gnomad FIN exome

AF:

0.00550

Gnomad NFE exome

AF:

0.00261

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00317

AC:

4634

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

2274

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.0195

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00298

Gnomad4 FIN exome

AF:

0.00391

Gnomad4 NFE exome

AF:

0.00289

Gnomad4 OTH exome

AF:

0.00320

GnomAD4 genome

AF:

0.00701

AC:

1067

AN:

152210

Hom.:

Cov.:

AF XY:

0.00676

AC XY:

503

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0174

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00642

Gnomad4 NFE

AF:

0.00285

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00289

Hom.:

Bravo

AF:

0.00717

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.0191

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00378

AC:

459

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00243

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 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

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

0.24

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.38

MutationAssessor

Pathogenic

4.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-7.2

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.62

MVP

0.88

MPC

0.047

ClinPred

0.090

GERP RS

2.9

Varity_R

0.74

gMVP

0.14

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

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