10-95045864-T-A

Position:

• chr10-95045864-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000770.3(CYP2C8):​c.907A>T​(p.Ser303Cys) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP2C8 NM_000770.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.978

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C8	NM_000770.3	c.907A>T	p.Ser303Cys	missense_variant	6/9	ENST00000371270.6	NP_000761.3
CYP2C8	NM_001198853.1	c.697A>T	p.Ser233Cys	missense_variant	6/9		NP_001185782.1
CYP2C8	NM_001198855.1	c.697A>T	p.Ser233Cys	missense_variant	7/10		NP_001185784.1
CYP2C8	NM_001198854.1	c.601A>T	p.Ser201Cys	missense_variant	5/8		NP_001185783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6	c.907A>T	p.Ser303Cys	missense_variant	6/9	1	NM_000770.3	ENSP00000360317.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 05, 2024

The c.907A>T (p.S303C) alteration is located in exon 6 (coding exon 6) of the CYP2C8 gene. This alteration results from a A to T substitution at nucleotide position 907, causing the serine (S) at amino acid position 303 to be replaced by a cysteine (C). 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	0.32
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	.;.;.;T;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	4.7	.;.;.;H;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.5	.;D;.;D;.
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	.;D;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.68
MutPred		0.89		.;.;.;Loss of disorder (P = 0.0258);.;
MVP		0.83
MPC		0.18
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.18

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: chr10-96805621;