Genetic Variant NM_000771.4:c.168+1373T>C (chr10-94940223-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.168+1373T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 152,278 control chromosomes in the GnomAD database, including 242 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 ( 242 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

CYP2C9
NM_000771.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.516

Publications

7 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:

MTND4P20 (HGNC:42207): (MT-ND4 pseudogene 20)

MTND4P20 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=-0.94).

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.168+1373T>C		intron_variant	Intron 1 of 8	ENST00000260682.8	NP_000762.2	P11712-1S5RV20

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP2C9	ENST00000260682.8 link	c.168+1373T>C	intron_variant	Intron 1 of 8	1	NM_000771.4	ENSP00000260682.6	P11712-1
CYP2C9	ENST00000461906.1 link	c.168+1373T>C	intron_variant	Intron 1 of 2	1		ENSP00000495649.1	P11712-2
CYP2C9	ENST00000643112.1 link	n.168+1373T>C	intron_variant	Intron 1 of 7			ENSP00000496202.1	A0A2R8YF67
MTND4P20	ENST00000424125.1 link	n.*30A>G	downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.0497

AC:

7560

AN:

152160

Hom.:

243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0492

Gnomad ASJ

AF:

0.0824

Gnomad EAS

AF:

0.0314

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.0557

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0663

Gnomad OTH

AF:

0.0535

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.0496

AC:

7553

AN:

152278

Hom.:

242

Cov.:

AF XY:

0.0502

AC XY:

3742

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0132

AC:

548

AN:

41568

American (AMR)

AF:

0.0491

AC:

750

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0824

AC:

286

AN:

3470

East Asian (EAS)

AF:

0.0314

AC:

163

AN:

5184

South Asian (SAS)

AF:

0.114

AC:

552

AN:

4828

European-Finnish (FIN)

AF:

0.0557

AC:

591

AN:

10618

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0663

AC:

4507

AN:

68010

Other (OTH)

AF:

0.0520

AC:

110

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

360

720

1080

1440

1800

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:

0.0559

Hom.:

150

Bravo

AF:

0.0465

Asia WGS

AF:

0.0760

AC:

266

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

2.1

(source)

DANN

Benign

0.48

PhyloP100

0.52

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over