Variant 10-95038964-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000770.3(CYP2C8):c.1224C>A(p.Asp408Glu) 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 1,461,428 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: 0.339

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:

CYP2C8 (HGNC:):

CYP2C8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C8	NM_000770.3 linkuse as main transcript	c.1224C>A	p.Asp408Glu	missense_variant	8/9	ENST00000371270.6	NP_000761.3	P10632-1
CYP2C8	NM_001198853.1 linkuse as main transcript	c.1014C>A	p.Asp338Glu	missense_variant	8/9		NP_001185782.1	P10632B7Z1F5
CYP2C8	NM_001198855.1 linkuse as main transcript	c.1014C>A	p.Asp338Glu	missense_variant	9/10		NP_001185784.1	P10632B7Z1F5
CYP2C8	NM_001198854.1 linkuse as main transcript	c.918C>A	p.Asp306Glu	missense_variant	7/8		NP_001185783.1	P10632-2B7Z1F5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6 linkuse as main transcript	c.1224C>A	p.Asp408Glu	missense_variant	8/9	1	NM_000770.3	ENSP00000360317.3		P10632-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461428

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.1224C>A (p.D408E) alteration is located in exon 8 (coding exon 8) of the CYP2C8 gene. This alteration results from a C to A substitution at nucleotide position 1224, causing the aspartic acid (D) at amino acid position 408 to be replaced by a glutamic acid (E). 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

0.41

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

.;.;.;T

Eigen

Benign

0.055

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.67

.;T;T;T

M_CAP

Benign

0.0022

MetaRNN

Uncertain

0.67

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.4

.;.;.;M

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.5

.;D;.;D

REVEL

Benign

0.13

Sift

Uncertain

0.015

.;D;.;D

Sift4G

Uncertain

0.032

D;D;D;D

Polyphen

0.95

.;.;.;P

Vest4

0.42

MutPred

0.64

.;.;.;Gain of disorder (P = 0.1819);

MVP

0.58

MPC

0.12

ClinPred

0.97

GERP RS

2.1

Varity_R

0.71

gMVP

0.049

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over