Genetic Variant CYP2C9:p.Pro489Ser (chr10-94989020-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_000771.4(CYP2C9):c.1465C>T(p.Pro489Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,944 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

CYP2C9
NM_000771.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.40

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 10-94989020-C-T is Pathogenic according to our data. Variant chr10-94989020-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.015488237). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 253 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C9	NM_000771.4 link	c.1465C>T	p.Pro489Ser	missense_variant	Exon 9 of 9	ENST00000260682.8	NP_000762.2	P11712-1S5RV20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP2C9	ENST00000260682.8 link	c.1465C>T	p.Pro489Ser	missense_variant	Exon 9 of 9	1	NM_000771.4	ENSP00000260682.6	P11712-1
CYP2C9	ENST00000643112.1 link	n.*474C>T		non_coding_transcript_exon_variant	Exon 8 of 8			ENSP00000496202.1	A0A2R8YF67
CYP2C9	ENST00000643112.1 link	n.*474C>T		3_prime_UTR_variant	Exon 8 of 8			ENSP00000496202.1	A0A2R8YF67

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

253

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00253

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00174

AC:

437

AN:

251320

Hom.:

AF XY:

0.00163

AC XY:

222

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00286

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00214

AC:

3127

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

1505

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00187

Gnomad4 NFE exome

AF:

0.00251

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00166

AC:

253

AN:

152318

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00253

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00187

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00191

AC:

232

EpiCase

AF:

0.00196

EpiControl

AF:

0.00213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

Eigen

Benign

0.036

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.84

M_CAP

Benign

0.0042

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-6.9

REVEL

Benign

0.11

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.15

MVP

0.56

MPC

0.030

ClinPred

0.10

GERP RS

2.5

Varity_R

0.73

gMVP

0.46

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over