rs72558189

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000771.4(CYP2C9):​c.374G>A​(p.Arg125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,954 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00082 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 43 hom. )

Consequence

CYP2C9
NM_000771.4 missense

Scores

1
4
13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.78

Publications

43 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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.023801684).
BP6
Variant 10-94942234-G-A is Benign according to our data. Variant chr10-94942234-G-A is described in ClinVar as [Benign]. Clinvar id is 1167372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000821 (125/152254) while in subpopulation SAS AF = 0.0207 (100/4820). AF 95% confidence interval is 0.0175. There are 2 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 125 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYP2C9NM_000771.4 linkc.374G>A p.Arg125His missense_variant Exon 3 of 9 ENST00000260682.8 NP_000762.2 P11712-1S5RV20

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYP2C9ENST00000260682.8 linkc.374G>A p.Arg125His missense_variant Exon 3 of 9 1 NM_000771.4 ENSP00000260682.6 P11712-1

Frequencies

GnomAD3 genomes
AF:
0.000828
AC:
126
AN:
152136
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.0209
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00243
AC:
610
AN:
251246
AF XY:
0.00355
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.000109
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00122
AC:
1790
AN:
1461700
Hom.:
43
Cov.:
33
AF XY:
0.00181
AC XY:
1316
AN XY:
727156
show subpopulations
African (AFR)
AF:
0.000179
AC:
6
AN:
33470
American (AMR)
AF:
0.000179
AC:
8
AN:
44696
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26132
East Asian (EAS)
AF:
0.000101
AC:
4
AN:
39682
South Asian (SAS)
AF:
0.0187
AC:
1616
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.000694
AC:
4
AN:
5762
European-Non Finnish (NFE)
AF:
0.0000782
AC:
87
AN:
1111904
Other (OTH)
AF:
0.00106
AC:
64
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
163
326
489
652
815
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
24
48
72
96
120
<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:
0.000821
AC:
125
AN:
152254
Hom.:
2
Cov.:
32
AF XY:
0.00128
AC XY:
95
AN XY:
74430
show subpopulations
African (AFR)
AF:
0.0000962
AC:
4
AN:
41572
American (AMR)
AF:
0.000655
AC:
10
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000387
AC:
2
AN:
5170
South Asian (SAS)
AF:
0.0207
AC:
100
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000132
AC:
9
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
7
14
21
28
35
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<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:
0.000313
Hom.:
0
Bravo
AF:
0.000314
ExAC
AF:
0.00295
AC:
358
EpiCase
AF:
0.000164
EpiControl
AF:
0.000178

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Aug 21, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
.;T
Eigen
Benign
0.11
Eigen_PC
Benign
-0.023
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.78
T;T
MetaRNN
Benign
0.024
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Pathogenic
3.3
M;M
PhyloP100
2.8
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-4.0
.;D
REVEL
Benign
0.15
Sift
Benign
0.055
.;T
Sift4G
Uncertain
0.044
.;D
Polyphen
0.76
.;P
Vest4
0.37
MutPred
0.81
Loss of phosphorylation at S127 (P = 0.0594);Loss of phosphorylation at S127 (P = 0.0594);
MVP
0.52
MPC
0.017
ClinPred
0.17
T
GERP RS
2.4
Varity_R
0.29
gMVP
0.14
Mutation Taster
=77/23
polymorphism

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

Other links and lift over

dbSNP: rs72558189; hg19: chr10-96701991; API