Variant 10-94942234-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM5PP3_StrongBS2

The NM_000771.4(CYP2C9):c.374G>T(p.Arg125Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

CYP2C9
NM_000771.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.78

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-94942234-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

BS2

High AC in GnomAdExome4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C9	NM_000771.4 linkuse as main transcript	c.374G>T	p.Arg125Leu	missense_variant	3/9	ENST00000260682.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C9	ENST00000260682.8 linkuse as main transcript	c.374G>T	p.Arg125Leu	missense_variant	3/9	1	NM_000771.4	P1	P11712-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251246

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461700

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000248

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;T

Eigen

Uncertain

0.44

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.0044

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-0.75

MutationAssessor

Pathogenic

4.8

H;H

MutationTaster

Benign

0.99

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-5.9

.;D

REVEL

Benign

0.24

Sift

Uncertain

0.0010

.;D

Sift4G

Pathogenic

0.0010

.;D

Polyphen

0.98

.;D

Vest4

0.90

MutPred

0.82

Loss of phosphorylation at S127 (P = 0.0528);Loss of phosphorylation at S127 (P = 0.0528);

MVP

0.62

MPC

0.049

ClinPred

1.0

GERP RS

2.4

Varity_R

0.80

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over