10-94695040-A-G

Position:

• chr10-94695040-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000772.3(CYP2C18):​c.605A>G​(p.Asn202Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,613,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: CYP2C18 NM_000772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.452

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.074300826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C18	NM_000772.3	c.605A>G	p.Asn202Ser	missense_variant	4/9	ENST00000285979.11	NP_000763.1
CYP2C18	NM_001128925.2	c.605A>G	p.Asn202Ser	missense_variant	4/8		NP_001122397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C18	ENST00000285979.11	c.605A>G	p.Asn202Ser	missense_variant	4/9	1	NM_000772.3	ENSP00000285979.6
CYP2C18	ENST00000339022.6	c.605A>G	p.Asn202Ser	missense_variant	4/8	1		ENSP00000341293.5
ENSG00000276490	ENST00000464755.1	n.245A>G		non_coding_transcript_exon_variant	2/14	2		ENSP00000483243.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000144 AC: 36 AN: 250530 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135444

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000302 AC: 441 AN: 1460764 Hom.: 0 Cov.: 30 AF XY: 0.000278 AC XY: 202 AN XY: 726684

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000376

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74490

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000335 Hom.: 1

Bravo AF: 0.000268

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.605A>G (p.N202S) alteration is located in exon 4 (coding exon 4) of the CYP2C18 gene. This alteration results from a A to G substitution at nucleotide position 605, causing the asparagine (N) at amino acid position 202 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	Benign	0.094
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.4	M;M
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.063
Sift	Uncertain	0.0090	D;T
Sift4G	Benign	0.12	T;T
Polyphen		0.27	B;.
Vest4		0.090
MVP		0.67
MPC		0.017
ClinPred		0.084	T
GERP RS		2.2
Varity_R		0.20
gMVP		0.074

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: rs137908489; hg19: chr10-96454797;