10-95039031-G-A

Variant names:

• chr10-95039031-G-A
• rs2032944739
• NM_000770.3:c.1157C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_000770.3(CYP2C8):​c.1157C>T​(p.Thr386Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CYP2C8 NM_000770.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.43
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21939221).
• BP6: Variant 10-95039031-G-A is Benign according to our data. Variant chr10-95039031-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3837860.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C8	NM_000770.3	c.1157C>T	p.Thr386Ile	missense_variant	Exon 8 of 9	ENST00000371270.6	NP_000761.3
CYP2C8	NM_001198853.1	c.947C>T	p.Thr316Ile	missense_variant	Exon 8 of 9		NP_001185782.1
CYP2C8	NM_001198855.1	c.947C>T	p.Thr316Ile	missense_variant	Exon 9 of 10		NP_001185784.1
CYP2C8	NM_001198854.1	c.851C>T	p.Thr284Ile	missense_variant	Exon 7 of 8		NP_001185783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6	c.1157C>T	p.Thr386Ile	missense_variant	Exon 8 of 9	1	NM_000770.3	ENSP00000360317.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461150 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726946

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111356

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 14, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.42
DANN	Benign	0.65
DEOGEN2	Benign	0.26	.;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.34	.;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	.;.;.;L
PhyloP100		-1.4
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.6	.;D;.;D
REVEL	Benign	0.044
Sift	Benign	0.051	.;T;.;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0070	.;.;.;B
Vest4		0.16
MutPred		0.29		.;.;.;Loss of glycosylation at T386 (P = 0.0977);
MVP		0.25
MPC		0.024
ClinPred		0.13	T
GERP RS		-4.0
Varity_R		0.13
gMVP		0.087
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2032944739; hg19: chr10-96798788;