10-95038998-T-C

Variant names:

• chr10-95038998-T-C
• NM_000770.3:c.1190A>G

Variant summary

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

The NM_000770.3(CYP2C8):​c.1190A>G​(p.Asp397Gly) variant causes a missense change. 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: 3.77

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 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, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C8	NM_000770.3	c.1190A>G	p.Asp397Gly	missense_variant	Exon 8 of 9	ENST00000371270.6	NP_000761.3
CYP2C8	NM_001198853.1	c.980A>G	p.Asp327Gly	missense_variant	Exon 8 of 9		NP_001185782.1
CYP2C8	NM_001198855.1	c.980A>G	p.Asp327Gly	missense_variant	Exon 9 of 10		NP_001185784.1
CYP2C8	NM_001198854.1	c.884A>G	p.Asp295Gly	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.1190A>G	p.Asp397Gly	missense_variant	Exon 8 of 9	1	NM_000770.3	ENSP00000360317.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1190A>G (p.D397G) alteration is located in exon 8 (coding exon 8) of the CYP2C8 gene. This alteration results from a A to G substitution at nucleotide position 1190, causing the aspartic acid (D) at amino acid position 397 to be replaced by a glycine (G). 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	0.30
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;.;.;T
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.79	.;T;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	4.2	.;.;.;H
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-6.0	.;D;.;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0070	.;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.94	.;.;.;P
Vest4		0.76
MutPred		0.92		.;.;.;Loss of stability (P = 0.0652);
MVP		0.80
MPC		0.12
ClinPred		0.82	D
GERP RS		2.8
Varity_R		0.44
gMVP		0.25

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: chr10-96798755;