rs2281891

chr10-94733301-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000772.3(CYP2C18):c.1154C>T(p.Thr385Met) variant causes a missense change. The variant allele was found at a frequency of 0.163 in 1,610,372 control chromosomes in the GnomAD database, including 23,809 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2316 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21493 hom.)
• Consequence: CYP2C18 NM_000772.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.35

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006385386).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C18	NM_000772.3	c.1154C>T	p.Thr385Met	missense_variant	8/9	ENST00000285979.11
CYP2C18	NM_001128925.2	c.977C>T	p.Thr326Met	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C18	ENST00000285979.11	c.1154C>T	p.Thr385Met	missense_variant	8/9	1	NM_000772.3	P1
CYP2C18	ENST00000339022.6	c.977C>T	p.Thr326Met	missense_variant	7/8	1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25299 AN: 151886 Hom.: 2312 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.147

GnomAD3 exomes AF: 0.178 AC: 44490 AN: 249382 Hom.: 4694 AF XY: 0.186 AC XY: 24994 AN XY: 134710

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.310

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.163 AC: 237444 AN: 1458368 Hom.: 21493 Cov.: 32 AF XY: 0.167 AC XY: 121487 AN XY: 725478

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.323

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.167 AC: 25316 AN: 152004 Hom.: 2316 Cov.: 32 AF XY: 0.170 AC XY: 12660 AN XY: 74270

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.152

Alfa AF: 0.148 Hom.: 3260

Bravo AF: 0.159

TwinsUK AF: 0.151 AC: 561

ALSPAC AF: 0.150 AC: 579

ESP6500AA AF: 0.164 AC: 721

ESP6500EA AF: 0.148 AC: 1275

ExAC AF: 0.183 AC: 22226

Asia WGS AF: 0.303 AC: 1050 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.148

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	P;P
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		1.0	D;.
Vest4		0.15
MPC		0.12
ClinPred		0.11	T
GERP RS		0.10
Varity_R		0.21
gMVP		0.38

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

Other links and lift over

dbSNP: rs1126545; hg19: chr10-96493058; COSMIC: COSV53669749;