chr10-94695028-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000772.3(CYP2C18):​c.593T>C​(p.Met198Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M198L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CYP2C18
NM_000772.3 missense

Scores

1
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.15
Variant links:
Genes affected
CYP2C18 (HGNC:2620): (cytochrome P450 family 2 subfamily C member 18) 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 but its specific substrate has not yet been determined. The gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. An additional gene, CYP2C17, was once thought to exist; however, CYP2C17 is now considered an artefact based on a chimera of CYP2C18 and CYP2C19. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYP2C18NM_000772.3 linkc.593T>C p.Met198Thr missense_variant Exon 4 of 9 ENST00000285979.11 NP_000763.1 P33260-1Q7Z348
CYP2C18NM_001128925.2 linkc.593T>C p.Met198Thr missense_variant Exon 4 of 8 NP_001122397.1 P33260-2Q7Z348

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYP2C18ENST00000285979.11 linkc.593T>C p.Met198Thr missense_variant Exon 4 of 9 1 NM_000772.3 ENSP00000285979.6 P33260-1
CYP2C18ENST00000339022.6 linkc.593T>C p.Met198Thr missense_variant Exon 4 of 8 1 ENSP00000341293.5 P33260-2
ENSG00000276490ENST00000464755.1 linkn.233T>C non_coding_transcript_exon_variant Exon 2 of 14 2 ENSP00000483243.1 A0A087X0B3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460950
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726766
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33464
American (AMR)
AF:
0.00
AC:
0
AN:
44682
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39636
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86168
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53402
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5266
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111864
Other (OTH)
AF:
0.00
AC:
0
AN:
60336
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
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:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 26, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.593T>C (p.M198T) alteration is located in exon 4 (coding exon 4) of the CYP2C18 gene. This alteration results from a T to C substitution at nucleotide position 593, causing the methionine (M) at amino acid position 198 to be replaced by a threonine (T). 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
0.40
BayesDel_addAF
Benign
-0.079
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
19
DANN
Benign
0.86
DEOGEN2
Benign
0.25
T;.
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.86
D;T
M_CAP
Uncertain
0.14
D
MetaRNN
Uncertain
0.47
T;T
MetaSVM
Uncertain
0.058
D
MutationAssessor
Uncertain
2.4
M;M
PhyloP100
7.2
PROVEAN
Pathogenic
-4.4
D;D
REVEL
Benign
0.28
Sift
Uncertain
0.017
D;T
Sift4G
Uncertain
0.0090
D;D
Polyphen
0.075
B;.
Vest4
0.27
MutPred
0.71
Loss of stability (P = 0.048);Loss of stability (P = 0.048);
MVP
0.76
MPC
0.097
ClinPred
0.77
D
GERP RS
4.5
Varity_R
0.66
gMVP
0.28
Mutation Taster
=100/0
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: rs1847088140; hg19: chr10-96454785; API