Genetic Variant CYP2C9:c.1291+101T>C (chr10-94986275-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 NM_000771.4(CYP2C9):c.1291+101T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00696 in 1,206,132 control chromosomes in the GnomAD database, including 367 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 0.030 ( 242 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 125 hom. )

Consequence

CYP2C9
NM_000771.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.766

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=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 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.1291+101T>C		intron	N/A	NP_000762.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C9	ENST00000260682.8	TSL:1 MANE Select	c.1291+101T>C		intron	N/A	ENSP00000260682.6
	CYP2C9	ENST00000643112.1		n.*300+101T>C		intron	N/A	ENSP00000496202.1

Frequencies

GnomAD3 genomes

AF:

0.0305

AC:

4638

AN:

152160

Hom.:

242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0162

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.0215

GnomAD4 exome

AF:

0.00357

AC:

3757

AN:

1053856

Hom.:

125

AF XY:

0.00305

AC XY:

1654

AN XY:

541536

show subpopulations

African (AFR)

AF:

0.0997

AC:

2522

AN:

25288

American (AMR)

AF:

0.00838

AC:

345

AN:

41172

Ashkenazi Jewish (ASJ)

AF:

0.00125

AC:

AN:

23240

East Asian (EAS)

AF:

0.00

AC:

AN:

37262

South Asian (SAS)

AF:

0.000158

AC:

AN:

75984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45476

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

4760

European-Non Finnish (NFE)

AF:

0.000547

AC:

412

AN:

753602

Other (OTH)

AF:

0.00812

AC:

382

AN:

47072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

194

388

582

776

970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0304

AC:

4635

AN:

152276

Hom.:

242

Cov.:

AF XY:

0.0290

AC XY:

2163

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.103

AC:

4292

AN:

41536

American (AMR)

AF:

0.0162

AC:

247

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68016

Other (OTH)

AF:

0.0213

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

208

417

625

834

1042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0118

Hom.:

Bravo

AF:

0.0353

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.7

(source)

DANN

Benign

0.73

PhyloP100

0.77

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over