dbSNP rs1057911: CYP2C9:p.Gly475Gly (chr10-94988980-A-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000771.4(CYP2C9):c.1425A>T(p.Gly475Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0635 in 1,613,872 control chromosomes in the GnomAD database, including 3,708 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.050 ( 245 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3463 hom. )

Consequence

CYP2C9
NM_000771.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.70

Publications

45 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP7

Synonymous conserved (PhyloP=-2.7 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C9	NM_000771.4 link	c.1425A>T	p.Gly475Gly	synonymous_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.1425A>T	p.Gly475Gly	synonymous_variant	Exon 9 of 9	1	NM_000771.4	ENSP00000260682.6	P11712-1
CYP2C9	ENST00000643112.1 link	n.*434A>T		non_coding_transcript_exon_variant	Exon 8 of 8			ENSP00000496202.1	A0A2R8YF67
CYP2C9	ENST00000643112.1 link	n.*434A>T		3_prime_UTR_variant	Exon 8 of 8			ENSP00000496202.1	A0A2R8YF67

Frequencies

GnomAD3 genomes

AF:

0.0497

AC:

7560

AN:

152082

Hom.:

246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0131

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0493

Gnomad ASJ

AF:

0.0827

Gnomad EAS

AF:

0.0316

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.0562

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0663

Gnomad OTH

AF:

0.0531

GnomAD2 exomes

AF:

0.0631

AC:

15870

AN:

251376

AF XY:

0.0683

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.0380

Gnomad ASJ exome

AF:

0.0840

Gnomad EAS exome

AF:

0.0337

Gnomad FIN exome

AF:

0.0626

Gnomad NFE exome

AF:

0.0684

Gnomad OTH exome

AF:

0.0633

GnomAD4 exome

AF:

0.0649

AC:

94874

AN:

1461672

Hom.:

3463

Cov.:

AF XY:

0.0662

AC XY:

48160

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.0146

AC:

487

AN:

33454

American (AMR)

AF:

0.0395

AC:

1768

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0833

AC:

2177

AN:

26128

East Asian (EAS)

AF:

0.0301

AC:

1196

AN:

39696

South Asian (SAS)

AF:

0.110

AC:

9483

AN:

86256

European-Finnish (FIN)

AF:

0.0627

AC:

3349

AN:

53420

Middle Eastern (MID)

AF:

0.0744

AC:

429

AN:

5764

European-Non Finnish (NFE)

AF:

0.0648

AC:

72093

AN:

1111864

Other (OTH)

AF:

0.0645

AC:

3892

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

5482

10963

16445

21926

27408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2604

5208

7812

10416

13020

<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:

0.0496

AC:

7554

AN:

152200

Hom.:

245

Cov.:

AF XY:

0.0502

AC XY:

3736

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0131

AC:

544

AN:

41534

American (AMR)

AF:

0.0492

AC:

751

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0827

AC:

287

AN:

3472

East Asian (EAS)

AF:

0.0317

AC:

164

AN:

5178

South Asian (SAS)

AF:

0.114

AC:

551

AN:

4822

European-Finnish (FIN)

AF:

0.0562

AC:

596

AN:

10604

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0663

AC:

4506

AN:

67996

Other (OTH)

AF:

0.0516

AC:

109

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

371

742

1113

1484

1855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0647

Hom.:

196

Bravo

AF:

0.0465

Asia WGS

AF:

0.0770

AC:

267

AN:

3478

EpiCase

AF:

0.0713

EpiControl

AF:

0.0737

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.23

(source)

DANN

Benign

0.46

PhyloP100

-2.7

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over