NM_000771.4:c.430C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000771.4(CYP2C9):c.430C>T(p.Arg144Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,772 control chromosomes in the GnomAD database, including 11,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,drug response,other (★★).

Frequency

Genomes: 𝑓 0.088 ( 755 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11216 hom. )

Consequence

CYP2C9
NM_000771.4 missense

Scores

Clinical Significance

Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:1O:7

Conservation

PhyloP100: -0.0520

Publications

898 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008835256).

BP6

Variant 10-94942290-C-T is Benign according to our data. Variant chr10-94942290-C-T is described in ClinVar as Likely_benign|drug_response|other. ClinVar VariationId is 8409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000771.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C9	NM_000771.4	MANE Select	c.430C>T	p.Arg144Cys	missense	Exon 3 of 9	NP_000762.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP2C9	ENST00000260682.8	TSL:1 MANE Select	c.430C>T	p.Arg144Cys	missense	Exon 3 of 9	ENSP00000260682.6
CYP2C9	ENST00000461906.1	TSL:1	c.430C>T	p.Arg144Cys	missense	Exon 3 of 3	ENSP00000495649.1
CYP2C9	ENST00000880948.1		c.430C>T	p.Arg144Cys	missense	Exon 3 of 9	ENSP00000551007.1

Frequencies

GnomAD3 genomes

AF:

0.0882

AC:

13405

AN:

152046

Hom.:

755

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0236

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.0980

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0388

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.112

GnomAD2 exomes

AF:

0.0920

AC:

23117

AN:

251228

AF XY:

0.0940

show subpopulations

Gnomad AFR exome

AF:

0.0223

Gnomad AMR exome

AF:

0.0680

Gnomad ASJ exome

AF:

0.136

Gnomad EAS exome

AF:

0.000436

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.128

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.118

AC:

171842

AN:

1461608

Hom.:

11216

Cov.:

AF XY:

0.116

AC XY:

84405

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0195

AC:

652

AN:

33460

American (AMR)

AF:

0.0722

AC:

3227

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

3599

AN:

26124

East Asian (EAS)

AF:

0.000227

AC:

AN:

39688

South Asian (SAS)

AF:

0.0490

AC:

4230

AN:

86254

European-Finnish (FIN)

AF:

0.113

AC:

6063

AN:

53420

Middle Eastern (MID)

AF:

0.120

AC:

693

AN:

5764

European-Non Finnish (NFE)

AF:

0.132

AC:

146976

AN:

1111836

Other (OTH)

AF:

0.106

AC:

6393

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

9812

19625

29437

39250

49062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5244

10488

15732

20976

26220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0881

AC:

13400

AN:

152164

Hom.:

755

Cov.:

AF XY:

0.0870

AC XY:

6471

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0235

AC:

977

AN:

41536

American (AMR)

AF:

0.0978

AC:

1493

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

470

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.0388

AC:

187

AN:

4820

European-Finnish (FIN)

AF:

0.118

AC:

1249

AN:

10586

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.127

AC:

8609

AN:

67998

Other (OTH)

AF:

0.110

AC:

233

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

609

1218

1827

2436

3045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.102

Hom.:

499

Bravo

AF:

0.0859

TwinsUK

AF:

0.136

AC:

503

ALSPAC

AF:

0.134

AC:

515

ESP6500AA

AF:

0.0268

AC:

118

ESP6500EA

AF:

0.131

AC:

1124

ExAC

AF:

0.0914

AC:

11093

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.132

EpiControl

AF:

0.131

ClinVar

ClinVar submissions as Germline

Significance:Likely benign; drug response; other

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Flurbiprofen response (1)

Lesinurad response (1)

not provided (1)

Phenytoin response (1)

Piroxicam response (1)

Warfarin response (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Benign

-0.080

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0088

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.2

PhyloP100

-0.052

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.34

Sift

Uncertain

0.028

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.15

MPC

0.051

ClinPred

0.072

GERP RS

1.4

Varity_R

0.65

gMVP

0.20

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over