10-95043003-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000770.3(CYP2C8):​c.1036C>T​(p.Pro346Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CYP2C8
NM_000770.3 missense

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.25

Publications

2 publications found
Variant links:
Genes affected
CYP2C8 (HGNC:2622): (cytochrome P450 family 2 subfamily C member 8) 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 phenobarbital. The enzyme is known to metabolize many xenobiotics, including the anticonvulsive drug mephenytoin, benzo(a)pyrene, 7-ethyoxycoumarin, and the anti-cancer drug taxol. This gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYP2C8NM_000770.3 linkc.1036C>T p.Pro346Ser missense_variant Exon 7 of 9 ENST00000371270.6 NP_000761.3 P10632-1
CYP2C8NM_001198853.1 linkc.826C>T p.Pro276Ser missense_variant Exon 7 of 9 NP_001185782.1 P10632B7Z1F5
CYP2C8NM_001198855.1 linkc.826C>T p.Pro276Ser missense_variant Exon 8 of 10 NP_001185784.1 P10632B7Z1F5
CYP2C8NM_001198854.1 linkc.730C>T p.Pro244Ser missense_variant Exon 6 of 8 NP_001185783.1 P10632-2B7Z1F5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYP2C8ENST00000371270.6 linkc.1036C>T p.Pro346Ser missense_variant Exon 7 of 9 1 NM_000770.3 ENSP00000360317.3 P10632-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251462
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461842
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727232
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000450
AC:
5
AN:
1111970
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.408
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 11, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1036C>T (p.P346S) alteration is located in exon 7 (coding exon 7) of the CYP2C8 gene. This alteration results from a C to T substitution at nucleotide position 1036, causing the proline (P) at amino acid position 346 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.11
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.30
.;.;.;T;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
.;D;D;D;D
M_CAP
Benign
0.019
T
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Uncertain
0.52
D
MutationAssessor
Pathogenic
3.9
.;.;.;H;.
PhyloP100
9.2
PrimateAI
Benign
0.47
T
PROVEAN
Pathogenic
-7.3
.;D;.;D;.
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
.;D;.;D;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
1.0
.;.;.;D;.
Vest4
0.73
MutPred
0.91
.;.;.;Loss of stability (P = 0.0647);.;
MVP
0.89
MPC
0.18
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.94
gMVP
0.15
Mutation Taster
=32/68
disease causing

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: rs762895826; hg19: chr10-96802760; COSMIC: COSV100987959; COSMIC: COSV100987959; API