dbSNP rs1204450867: CYP2C8:p.Thr450Ser (chr10-95037252-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000770.3(CYP2C8):c.1349C>G(p.Thr450Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T450N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

CYP2C8
NM_000770.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.74

Publications

1 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3587549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C8	NM_000770.3 link	c.1349C>G	p.Thr450Ser	missense_variant	Exon 9 of 9	ENST00000371270.6	NP_000761.3	P10632-1
CYP2C8	NM_001198853.1 link	c.1139C>G	p.Thr380Ser	missense_variant	Exon 9 of 9		NP_001185782.1	P10632B7Z1F5
CYP2C8	NM_001198855.1 link	c.1139C>G	p.Thr380Ser	missense_variant	Exon 10 of 10		NP_001185784.1	P10632B7Z1F5
CYP2C8	NM_001198854.1 link	c.1043C>G	p.Thr348Ser	missense_variant	Exon 8 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.1349C>G	p.Thr450Ser	missense_variant	Exon 9 of 9	1	NM_000770.3	ENSP00000360317.3		P10632-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

.;.;.;T

Eigen

Benign

-0.039

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.72

.;T;T;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

.;.;.;M

PhyloP100

2.7

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.5

.;D;.;D

REVEL

Benign

0.12

Sift

Benign

0.068

.;T;.;T

Sift4G

Benign

0.095

T;T;T;T

Polyphen

0.92

.;.;.;P

Vest4

0.33

MutPred

0.70

.;.;.;Loss of helix (P = 0.4763);

MVP

0.50

MPC

0.15

ClinPred

0.94

GERP RS

2.8

Varity_R

0.57

gMVP

0.12

Mutation Taster

=74/26

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over