rs11572080

Positions:

• chr10-95067273-C-A
• chr10-95067273-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The ENST00000371270.6(CYP2C8):​c.416G>T​(p.Arg139Met) 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 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. R139K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP2C8 ENST00000371270.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.144

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-95067273-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.40088844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C8	NM_000770.3	c.416G>T	p.Arg139Met	missense_variant	3/9	ENST00000371270.6	NP_000761.3
CYP2C8	NM_001198853.1	c.206G>T	p.Arg69Met	missense_variant	3/9		NP_001185782.1
CYP2C8	NM_001198855.1	c.206G>T	p.Arg69Met	missense_variant	4/10		NP_001185784.1
CYP2C8	NM_001198854.1	c.110G>T	p.Arg37Met	missense_variant	2/8		NP_001185783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6	c.416G>T	p.Arg139Met	missense_variant	3/9	1	NM_000770.3	ENSP00000360317	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.27	.;.;.;T;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.88	.;D;D;D;D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.9	.;.;.;H;.
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.0	.;D;.;D;.
REVEL	Benign	0.18
Sift	Pathogenic	0.0	.;D;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.44
MutPred		0.58		.;.;.;Loss of methylation at K138 (P = 0.0223);.;
MVP		0.56
MPC		0.18
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.86
gMVP		0.13

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

Other links and lift over

dbSNP: rs11572080; hg19: chr10-96827030;