10-94706954-G-T

Position:

• chr10-94706954-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000772.3(CYP2C18):​c.813G>T​(p.Met271Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CYP2C18 NM_000772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26754114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C18	NM_000772.3	c.813G>T	p.Met271Ile	missense_variant	5/9	ENST00000285979.11	NP_000763.1
CYP2C18	NM_001128925.2	c.642+11877G>T		intron_variant			NP_001122397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C18	ENST00000285979.11	c.813G>T	p.Met271Ile	missense_variant	5/9	1	NM_000772.3	ENSP00000285979.6
CYP2C18	ENST00000339022.6	c.642+11877G>T		intron_variant		1		ENSP00000341293.5
ENSG00000276490	ENST00000464755.1	n.453G>T		non_coding_transcript_exon_variant	3/14	2		ENSP00000483243.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453582 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000547

EpiControl AF: 0.00

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

Oct 20, 2024

The c.813G>T (p.M271I) alteration is located in exon 5 (coding exon 5) of the CYP2C18 gene. This alteration results from a G to T substitution at nucleotide position 813, causing the methionine (M) at amino acid position 271 to be replaced by an isoleucine (I). 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	0.45
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.3	M
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.15
Sift	Benign	0.11	T
Sift4G	Benign	0.071	T
Polyphen		0.014	B
Vest4		0.24
MutPred		0.66		Loss of ubiquitination at K270 (P = 0.0432);
MVP		0.65
MPC		0.017
ClinPred		0.53	D
GERP RS		2.5
Varity_R		0.27
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-96466711;