Genetic Variant CYP2C9:c.*257T>C (chr10-94942606-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000461906.1(CYP2C9):c.*257T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0633 in 569,566 control chromosomes in the GnomAD database, including 1,389 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: 33)

Exomes 𝑓: 0.068 ( 1144 hom. )

Consequence

CYP2C9
ENST00000461906.1 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.186

Publications

3 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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.481+265T>C		intron_variant	Intron 3 of 8	ENST00000260682.8	NP_000762.2	P11712-1S5RV20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C9	ENST00000260682.8 link	c.481+265T>C		intron_variant	Intron 3 of 8	1	NM_000771.4	ENSP00000260682.6		P11712-1

Frequencies

GnomAD3 genomes

AF:

0.0497

AC:

7557

AN:

152182

Hom.:

246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0131

Gnomad AMI

AF:

0.0297

Gnomad AMR

AF:

0.0491

Gnomad ASJ

AF:

0.0827

Gnomad EAS

AF:

0.0316

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.0560

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0663

Gnomad OTH

AF:

0.0527

GnomAD4 exome

AF:

0.0683

AC:

28511

AN:

417266

Hom.:

1144

Cov.:

AF XY:

0.0700

AC XY:

15392

AN XY:

219752

show subpopulations

African (AFR)

AF:

0.0153

AC:

181

AN:

11798

American (AMR)

AF:

0.0460

AC:

806

AN:

17522

Ashkenazi Jewish (ASJ)

AF:

0.0823

AC:

1049

AN:

12740

East Asian (EAS)

AF:

0.0298

AC:

818

AN:

27470

South Asian (SAS)

AF:

0.110

AC:

4806

AN:

43656

European-Finnish (FIN)

AF:

0.0644

AC:

1674

AN:

25974

Middle Eastern (MID)

AF:

0.0843

AC:

149

AN:

1768

European-Non Finnish (NFE)

AF:

0.0693

AC:

17484

AN:

252378

Other (OTH)

AF:

0.0644

AC:

1544

AN:

23960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1299

2598

3897

5196

6495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

7551

AN:

152300

Hom.:

245

Cov.:

AF XY:

0.0502

AC XY:

3741

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0131

AC:

544

AN:

41582

American (AMR)

AF:

0.0489

AC:

748

AN:

15288

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:

552

AN:

4828

European-Finnish (FIN)

AF:

0.0560

AC:

595

AN:

10616

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0663

AC:

4507

AN:

68022

Other (OTH)

AF:

0.0512

AC:

108

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

382

764

1147

1529

1911

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:

0.0577

Hom.:

Bravo

AF:

0.0465

Asia WGS

AF:

0.0770

AC:

268

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

6.2

(source)

DANN

Benign

0.75

PhyloP100

0.19

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