Genetic Variant NM_000771.4:c.1291+53A>T (chr10-94986227-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000771.4(CYP2C9):c.1291+53A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0635 in 1,569,750 control chromosomes in the GnomAD database, including 3,622 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 ( 244 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3378 hom. )

Consequence

CYP2C9
NM_000771.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.32

Publications

8 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=-0.84).

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.1291+53A>T		intron_variant	Intron 8 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.1291+53A>T		intron_variant	Intron 8 of 8	1	NM_000771.4	ENSP00000260682.6		P11712-1
CYP2C9	ENST00000643112.1 link	n.*300+53A>T		intron_variant	Intron 7 of 7			ENSP00000496202.1		A0A2R8YF67

Frequencies

GnomAD3 genomes

AF:

0.0497

AC:

7550

AN:

152052

Hom.:

245

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0131

Gnomad AMI

AF:

0.0297

Gnomad AMR

AF:

0.0491

Gnomad ASJ

AF:

0.0824

Gnomad EAS

AF:

0.0316

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.0561

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0663

Gnomad OTH

AF:

0.0531

GnomAD4 exome

AF:

0.0650

AC:

92095

AN:

1417582

Hom.:

3378

AF XY:

0.0664

AC XY:

47012

AN XY:

708256

show subpopulations

African (AFR)

AF:

0.0147

AC:

479

AN:

32512

American (AMR)

AF:

0.0396

AC:

1761

AN:

44482

Ashkenazi Jewish (ASJ)

AF:

0.0831

AC:

2145

AN:

25810

East Asian (EAS)

AF:

0.0302

AC:

1189

AN:

39398

South Asian (SAS)

AF:

0.110

AC:

9379

AN:

85242

European-Finnish (FIN)

AF:

0.0631

AC:

3305

AN:

52410

Middle Eastern (MID)

AF:

0.0746

AC:

423

AN:

5670

European-Non Finnish (NFE)

AF:

0.0649

AC:

69605

AN:

1073158

Other (OTH)

AF:

0.0647

AC:

3809

AN:

58900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

4654

9307

13961

18614

23268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2480

4960

7440

9920

12400

<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:

7544

AN:

152168

Hom.:

244

Cov.:

AF XY:

0.0501

AC XY:

3730

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0131

AC:

544

AN:

41544

American (AMR)

AF:

0.0490

AC:

748

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0824

AC:

286

AN:

3470

East Asian (EAS)

AF:

0.0317

AC:

164

AN:

5176

South Asian (SAS)

AF:

0.114

AC:

548

AN:

4814

European-Finnish (FIN)

AF:

0.0561

AC:

594

AN:

10596

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0663

AC:

4505

AN:

67984

Other (OTH)

AF:

0.0516

AC:

109

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

379

758

1137

1516

1895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0595

Hom.:

Bravo

AF:

0.0465

Asia WGS

AF:

0.0770

AC:

268

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.25

(source)

DANN

Benign

0.63

PhyloP100

-1.3

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