rs2281891

Variant names:

• chr10-94733301-C-T
• rs1126545
• NM_000772.3:c.1154C>T

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 42 publications found

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]

ENSG00000276490 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CYP2C18	NM_000772.3	c.1154C>T	p.Thr385Met	missense_variant	Exon 8 of 9	ENST00000285979.11	NP_000763.1
CYP2C18	NM_001128925.2	c.977C>T	p.Thr326Met	missense_variant	Exon 7 of 8		NP_001122397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C18	ENST00000285979.11	c.1154C>T	p.Thr385Met	missense_variant	Exon 8 of 9	1	NM_000772.3	ENSP00000285979.6
CYP2C18	ENST00000339022.6	c.977C>T	p.Thr326Met	missense_variant	Exon 7 of 8	1		ENSP00000341293.5
ENSG00000276490	ENST00000464755.1	n.794C>T		non_coding_transcript_exon_variant	Exon 6 of 14	2		ENSP00000483243.1

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

GnomAD2 exomes AF: 0.178 AC: 44490 AN: 249382 AF XY: 0.186

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 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

African (AFR) AF: 0.179 AC: 5965 AN: 33348

American (AMR) AF: 0.105 AC: 4684 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3613 AN: 26024

East Asian (EAS) AF: 0.303 AC: 12010 AN: 39600

South Asian (SAS) AF: 0.323 AC: 27725 AN: 85842

European-Finnish (FIN) AF: 0.171 AC: 9115 AN: 53348

Middle Eastern (MID) AF: 0.109 AC: 624 AN: 5746

European-Non Finnish (NFE) AF: 0.148 AC: 163722 AN: 1109742

Other (OTH) AF: 0.166 AC: 9986 AN: 60238

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

African (AFR) AF: 0.174 AC: 7207 AN: 41444

American (AMR) AF: 0.129 AC: 1969 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 479 AN: 3470

East Asian (EAS) AF: 0.312 AC: 1608 AN: 5158

South Asian (SAS) AF: 0.330 AC: 1592 AN: 4818

European-Finnish (FIN) AF: 0.183 AC: 1935 AN: 10562

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10016 AN: 67970

Other (OTH) AF: 0.152 AC: 320 AN: 2112

Alfa AF: 0.152 Hom.: 6839

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;.
PhyloP100		4.3
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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