10-95067616-C-G

Variant names:

• chr10-95067616-C-G
• rs17851796
• NM_000770.3:c.244G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000770.3(CYP2C8):​c.244G>C​(p.Ala82Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP2C8 NM_000770.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.630
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C8	NM_000770.3	c.244G>C	p.Ala82Pro	missense_variant	Exon 2 of 9	ENST00000371270.6	NP_000761.3
CYP2C8	NM_001198853.1	c.34G>C	p.Ala12Pro	missense_variant	Exon 2 of 9		NP_001185782.1
CYP2C8	NM_001198855.1	c.34G>C	p.Ala12Pro	missense_variant	Exon 3 of 10		NP_001185784.1
CYP2C8	NM_001198854.1	c.26-259G>C		intron_variant	Intron 1 of 7		NP_001185783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6	c.244G>C	p.Ala82Pro	missense_variant	Exon 2 of 9	1	NM_000770.3	ENSP00000360317.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.81	.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.4	.;.;M
PhyloP100		0.63
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.0	.;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.011	.;.;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.98	.;.;D
Vest4		0.73
MutPred		0.77		.;.;Gain of disorder (P = 0.2069);
MVP		0.68
MPC		0.14
ClinPred		0.89	D
GERP RS		2.8
PromoterAI		0.024	Neutral
Varity_R		0.88
gMVP		0.45
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17851796; hg19: chr10-96827373;