10-94694992-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000772.3(CYP2C18):c.557G>A(p.Arg186Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,988 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 1 hom. )
Consequence
CYP2C18
NM_000772.3 missense
NM_000772.3 missense
Scores
3
4
11
Clinical Significance
Conservation
PhyloP100: 3.51
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.852
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYP2C18 | ENST00000285979.11 | c.557G>A | p.Arg186Gln | missense_variant | 4/9 | 1 | NM_000772.3 | ENSP00000285979.6 | ||
CYP2C18 | ENST00000339022.6 | c.557G>A | p.Arg186Gln | missense_variant | 4/8 | 1 | ENSP00000341293.5 | |||
ENSG00000276490 | ENST00000464755.1 | n.197G>A | non_coding_transcript_exon_variant | 2/14 | 2 | ENSP00000483243.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152014Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250786Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135522
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1460974Hom.: 1 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 726784
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152014Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74234
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 01, 2021 | The c.557G>A (p.R186Q) alteration is located in exon 4 (coding exon 4) of the CYP2C18 gene. This alteration results from a G to A substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Pathogenic
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;H
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of ubiquitination at K190 (P = 0.0992);Loss of ubiquitination at K190 (P = 0.0992);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at