10-94981301-C-G

Position:

chr10-94981301-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5BP4_StrongBS2

The ENST00000260682.8(CYP2C9):c.1080C>G(p.Asp360Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00059 in 1,613,930 control chromosomes in the GnomAD database, including 5 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D360N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0032 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

CYP2C9
ENST00000260682.8 missense

Scores

Clinical Significance

Benign/Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:2O:4

Conservation

PhyloP100: -1.47

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 Likely_benign. Variant got -6 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-94981299-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0100749135).

BS2

High AC in GnomAd4 at 490 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C9	NM_000771.4 linkuse as main transcript	c.1080C>G	p.Asp360Glu	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.1080C>G	p.Asp360Glu	missense_variant	7/9	1	NM_000771.4	ENSP00000260682	P1	P11712-1
CYP2C9	ENST00000643112.1 linkuse as main transcript	c.*89C>G		3_prime_UTR_variant, NMD_transcript_variant	6/8			ENSP00000496202

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

491

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000820

AC:

206

AN:

251170

Hom.:

AF XY:

0.000641

AC XY:

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000317

AC:

463

AN:

1461664

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

202

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.0101

Gnomad4 AMR exome

AF:

0.000627

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.000911

GnomAD4 genome

AF:

0.00322

AC:

490

AN:

152266

Hom.:

Cov.:

AF XY:

0.00324

AC XY:

241

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0112

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.00361

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00116

AC:

141

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign; drug response; other

Submissions summary: Benign:2Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	This variant is associated with the following publications: (PMID: 11455026, 25087612, 19204079, 23752738) -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2015	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2020	- -

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

Pathogenic

0.75

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.78

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

4.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.082

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.96

Vest4

0.30

MutPred

0.26

Gain of glycosylation at P363 (P = 0.0839);

MVP

0.52

MPC

0.049

ClinPred

0.14

GERP RS

-0.53

Varity_R

0.95

gMVP

0.063

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