10-95039038-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000770.3(CYP2C8):c.1150G>A(p.Gly384Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00129 in 1,613,100 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (8 hom.)
• Consequence: CYP2C8 NM_000770.3 missense, splice_region
• Scores: Splicing: ADA: 0.9918
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.98

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_benign. Variant got -6 ACMG points.

• BP6: Variant 10-95039038-C-T is Benign according to our data. Variant chr10-95039038-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 733649.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C8	NM_000770.3	c.1150G>A	p.Gly384Ser	missense_variant, splice_region_variant	8/9	ENST00000371270.6
CYP2C8	NM_001198853.1	c.940G>A	p.Gly314Ser	missense_variant, splice_region_variant	8/9
CYP2C8	NM_001198855.1	c.940G>A	p.Gly314Ser	missense_variant, splice_region_variant	9/10
CYP2C8	NM_001198854.1	c.844G>A	p.Gly282Ser	missense_variant, splice_region_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C8	ENST00000371270.6	c.1150G>A	p.Gly384Ser	missense_variant, splice_region_variant	8/9	1	NM_000770.3	P1

Frequencies

GnomAD3 genomes AF: 0.000730 AC: 111 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000955 AC: 240 AN: 251394 Hom.: 2 AF XY: 0.00114 AC XY: 155 AN XY: 135860

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000985

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00135 AC: 1970 AN: 1460898 Hom.: 8 Cov.: 30 AF XY: 0.00141 AC XY: 1027 AN XY: 726848

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000726 AC XY: 54 AN XY: 74416

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00110 Hom.: 1

Bravo AF: 0.000733

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00101

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.40	T
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.98	.;.;.;D
Vest4		0.50
MVP		0.88
MPC		0.12
ClinPred		0.64	D
GERP RS		4.0
Varity_R		0.66
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.030		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: rs143386810; hg19: chr10-96798795;