Genetic Variant CYP2C8:p.Leu255Val (chr10-95058391-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000770.3(CYP2C8):c.763C>G(p.Leu255Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CYP2C8
NM_000770.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.152

Publications

0 publications found

Variant links:

Genes affected

CYP2C8 (HGNC:2622): (cytochrome P450 family 2 subfamily C member 8) 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 and its expression is induced by phenobarbital. The enzyme is known to metabolize many xenobiotics, including the anticonvulsive drug mephenytoin, benzo(a)pyrene, 7-ethyoxycoumarin, and the anti-cancer drug taxol. This gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

CYP2C8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C8	NM_000770.3 link	c.763C>G	p.Leu255Val	missense_variant	Exon 5 of 9	ENST00000371270.6	NP_000761.3	P10632-1
CYP2C8	NM_001198853.1 link	c.553C>G	p.Leu185Val	missense_variant	Exon 5 of 9		NP_001185782.1	P10632B7Z1F5
CYP2C8	NM_001198855.1 link	c.553C>G	p.Leu185Val	missense_variant	Exon 6 of 10		NP_001185784.1	P10632B7Z1F5
CYP2C8	NM_001198854.1 link	c.457C>G	p.Leu153Val	missense_variant	Exon 4 of 8		NP_001185783.1	P10632-2B7Z1F5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6 link	c.763C>G	p.Leu255Val	missense_variant	Exon 5 of 9	1	NM_000770.3	ENSP00000360317.3		P10632-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461236

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111656

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.763C>G (p.L255V) alteration is located in exon 5 (coding exon 5) of the CYP2C8 gene. This alteration results from a C to G substitution at nucleotide position 763, causing the leucine (L) at amino acid position 255 to be replaced by a valine (V). 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

0.17

BayesDel_addAF

Benign

-0.0028

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

.;.;.;T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.74

.;T;T;T;T

M_CAP

Benign

0.0076

MetaRNN

Uncertain

0.50

T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Pathogenic

3.0

.;.;.;M;.

PhyloP100

-0.15

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.4

.;N;.;N;.

REVEL

Uncertain

0.29

Sift

Uncertain

0.015

.;D;.;D;.

Sift4G

Uncertain

0.016

D;D;D;D;D

Polyphen

0.16

.;.;.;B;.

Vest4

0.19

MutPred

0.82

.;.;.;Loss of stability (P = 0.1031);.;

MVP

0.57

MPC

0.027

ClinPred

0.40

GERP RS

-0.51

Varity_R

0.51

gMVP

0.067

Mutation Taster

=81/19

polymorphism

(source)

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

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10-95058391-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over