10-94942234-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000771.4(CYP2C9):ā€‹c.374G>Cā€‹(p.Arg125Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R125H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

CYP2C9
NM_000771.4 missense

Scores

6
5
8

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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, 0.956

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CYP2C9NM_000771.4 linkc.374G>C p.Arg125Pro missense_variant 3/9 ENST00000260682.8 NP_000762.2 P11712-1S5RV20

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYP2C9ENST00000260682.8 linkc.374G>C p.Arg125Pro missense_variant 3/91 NM_000771.4 ENSP00000260682.6 P11712-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251246
Hom.:
0
AF XY:
0.00000736
AC XY:
1
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461700
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
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:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Uncertain
0.076
D
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
.;T
Eigen
Uncertain
0.44
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.79
T;T
M_CAP
Benign
0.0042
T
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Benign
-0.75
T
MutationAssessor
Pathogenic
4.8
H;H
PrimateAI
Benign
0.33
T
PROVEAN
Pathogenic
-6.1
.;D
REVEL
Benign
0.23
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0010
.;D
Polyphen
1.0
.;D
Vest4
0.84
MutPred
0.82
Gain of catalytic residue at R125 (P = 0.0475);Gain of catalytic residue at R125 (P = 0.0475);
MVP
0.65
MPC
0.052
ClinPred
0.99
D
GERP RS
2.4
Varity_R
0.94
gMVP
0.52

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.

Other links and lift over

dbSNP: rs72558189; hg19: chr10-96701991; API