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rs1057910

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM5BP4_StrongBA1

The NM_000771.4(CYP2C9):c.1075A>C(p.Ile359Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0634 in 1,613,890 control chromosomes in the GnomAD database, including 3,705 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response,other (★★). 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. I359T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.049 ( 244 hom., cov: 32)
Exomes 𝑓: 0.065 ( 3461 hom. )

Consequence

CYP2C9
NM_000771.4 missense

Scores

1
17

Clinical Significance

drug response; other criteria provided, multiple submitters, no conflicts O:10

Conservation

PhyloP100: 0.278
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 Benign. Variant got -10 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr10-94981297-T-C is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.0023085773).
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/exons MANE UniProt
CYP2C9NM_000771.4 linkuse as main transcriptc.1075A>C p.Ile359Leu missense_variant 7/9 ENST00000260682.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP2C9ENST00000260682.8 linkuse as main transcriptc.1075A>C p.Ile359Leu missense_variant 7/91 NM_000771.4 P1P11712-1
CYP2C9ENST00000643112.1 linkuse as main transcriptc.*84A>C 3_prime_UTR_variant, NMD_transcript_variant 6/8

Frequencies

GnomAD3 genomes
AF:
0.0495
AC:
7523
AN:
152122
Hom.:
245
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0126
Gnomad AMI
AF:
0.0296
Gnomad AMR
AF:
0.0491
Gnomad ASJ
AF:
0.0827
Gnomad EAS
AF:
0.0307
Gnomad SAS
AF:
0.114
Gnomad FIN
AF:
0.0558
Gnomad MID
AF:
0.0728
Gnomad NFE
AF:
0.0662
Gnomad OTH
AF:
0.0526
GnomAD3 exomes
AF:
0.0631
AC:
15849
AN:
251154
Hom.:
662
AF XY:
0.0682
AC XY:
9258
AN XY:
135700
show subpopulations
Gnomad AFR exome
AF:
0.0123
Gnomad AMR exome
AF:
0.0381
Gnomad ASJ exome
AF:
0.0841
Gnomad EAS exome
AF:
0.0337
Gnomad SAS exome
AF:
0.110
Gnomad FIN exome
AF:
0.0626
Gnomad NFE exome
AF:
0.0685
Gnomad OTH exome
AF:
0.0630
GnomAD4 exome
AF:
0.0649
AC:
94818
AN:
1461650
Hom.:
3461
Cov.:
32
AF XY:
0.0662
AC XY:
48127
AN XY:
727130
show subpopulations
Gnomad4 AFR exome
AF:
0.0127
Gnomad4 AMR exome
AF:
0.0396
Gnomad4 ASJ exome
AF:
0.0833
Gnomad4 EAS exome
AF:
0.0301
Gnomad4 SAS exome
AF:
0.110
Gnomad4 FIN exome
AF:
0.0627
Gnomad4 NFE exome
AF:
0.0649
Gnomad4 OTH exome
AF:
0.0643
GnomAD4 genome
AF:
0.0494
AC:
7516
AN:
152240
Hom.:
244
Cov.:
32
AF XY:
0.0499
AC XY:
3715
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.0125
Gnomad4 AMR
AF:
0.0490
Gnomad4 ASJ
AF:
0.0827
Gnomad4 EAS
AF:
0.0307
Gnomad4 SAS
AF:
0.114
Gnomad4 FIN
AF:
0.0558
Gnomad4 NFE
AF:
0.0662
Gnomad4 OTH
AF:
0.0511
Alfa
AF:
0.0639
Hom.:
731
Bravo
AF:
0.0462
TwinsUK
AF:
0.0612
AC:
227
ALSPAC
AF:
0.0633
AC:
244
ESP6500AA
AF:
0.0143
AC:
63
ESP6500EA
AF:
0.0659
AC:
567
ExAC
AF:
0.0636
AC:
7727
Asia WGS
AF:
0.0770
AC:
268
AN:
3478
EpiCase
AF:
0.0713
EpiControl
AF:
0.0737

ClinVar

Significance: drug response; other
Submissions summary: Other:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Phenytoin response Other:2
drug response, no assertion criteria providedliterature onlyOMIMJun 15, 2012- -
drug response, no assertion criteria providedcase-controlEquipe Genetique des Anomalies du Developpement, Université de BourgogneSep 24, 2020May cause toxicity/ADR and poor metabolism/PK No CYP2C9 function
Warfarin response Other:2
drug response, no assertion criteria providedliterature onlyOMIMJun 15, 2012- -
drug response, no assertion criteria providedresearchPharmacogenomics Lab, Chungbuk National UniversityAug 31, 2010- likely responsive
Piroxicam response Other:1
drug response, criteria provided, single submittercurationMedical Genetics SummariesFeb 11, 2019Individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) have reduced clearance of piroxicam. Because the standard recommended dose of piroxicam may cause abnormally high plasma levels, a dose reduction should be considered for these individuals. Poor metabolizer
Glipizide response Other:1
drug response, no assertion criteria providedliterature onlyOMIMJun 15, 2012- -
Lesinurad response Other:1
drug response, criteria provided, single submittercurationMedical Genetics SummariesFeb 11, 2019Lesinurad should be used with caution in individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) because of increased exposure and an increased risk of side effects. Poor metabolizer
not provided Other:1
other, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 10, 2015- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Tolbutamide response Other:1
drug response, no assertion criteria providedliterature onlyOMIMDec 30, 2010- -
Flurbiprofen response Other:1
drug response, criteria provided, single submittercurationMedical Genetics SummariesFeb 11, 2019The dose of flurbiprofen should be reduced in individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) to avoid abnormally high plasma levels due to reduced metabolic clearance. Poor metabolizer

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.42
Cadd
Benign
17
Dann
Benign
0.96
DEOGEN2
Benign
0.096
T
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.090
N
LIST_S2
Benign
0.41
T
MetaRNN
Benign
0.0023
T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
0.97
N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.6
N
REVEL
Benign
0.070
Sift
Uncertain
0.013
D
Sift4G
Benign
0.36
T
Polyphen
0.0020
B
Vest4
0.085
MPC
0.019
ClinPred
0.011
T
GERP RS
1.1
Varity_R
0.64
gMVP
0.039

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: rs1057910; hg19: chr10-96741053; COSMIC: COSV53247682; API