chr10-95068566-T-C

Position:

chr10-95068566-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_001198855.1(CYP2C8):c.-43+1A>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,277,824 control chromosomes in the GnomAD database, including 47,401 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5055 hom., cov: 32)

Exomes 𝑓: 0.27 ( 42346 hom. )

Consequence

CYP2C8
NM_001198855.1 splice_donor, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.32

Variant links:

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 links:

CYP2C8 (HGNC:):

CYP2C8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.048297703 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.1, offset of 0 (no position change), new splice context is: ccaGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant 10-95068566-T-C is Benign according to our data. Variant chr10-95068566-T-C is described in ClinVar as [Benign]. Clinvar id is 402580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
CYP2C8	NM_000770.3 linkuse as main transcript	c.168+669A>G	intron_variant	ENST00000371270.6	NP_000761.3	P10632-1
CYP2C8	NM_001198853.1 linkuse as main transcript	c.-43+631A>G	intron_variant		NP_001185782.1	P10632B7Z1F5
CYP2C8	NM_001198855.1 linkuse as main transcript	c.-43+1A>G	splice_donor_variant, intron_variant		NP_001185784.1	P10632B7Z1F5
CYP2C8	NM_001198854.1 linkuse as main transcript	c.25+631A>G	intron_variant		NP_001185783.1	P10632-2B7Z1F5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6 linkuse as main transcript	c.168+669A>G		intron_variant		1	NM_000770.3	ENSP00000360317.3		P10632-1

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38335

AN:

151974

Hom.:

5047

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.326

Gnomad AMR

AF:

0.174

Gnomad ASJ

AF:

0.245

Gnomad EAS

AF:

0.0576

Gnomad SAS

AF:

0.234

Gnomad FIN

AF:

0.264

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.290

Gnomad OTH

AF:

0.246

GnomAD4 exome

AF:

0.270

AC:

303723

AN:

1125732

Hom.:

42346

Cov.:

AF XY:

0.269

AC XY:

148953

AN XY:

552876

show subpopulations

Gnomad4 AFR exome

AF:

0.235

Gnomad4 AMR exome

AF:

0.139

Gnomad4 ASJ exome

AF:

0.243

Gnomad4 EAS exome

AF:

0.0601

Gnomad4 SAS exome

AF:

0.240

Gnomad4 FIN exome

AF:

0.271

Gnomad4 NFE exome

AF:

0.281

Gnomad4 OTH exome

AF:

0.256

GnomAD4 genome

AF:

0.252

AC:

38373

AN:

152092

Hom.:

5055

Cov.:

AF XY:

0.248

AC XY:

18437

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.242

Gnomad4 AMR

AF:

0.174

Gnomad4 ASJ

AF:

0.245

Gnomad4 EAS

AF:

0.0577

Gnomad4 SAS

AF:

0.235

Gnomad4 FIN

AF:

0.264

Gnomad4 NFE

AF:

0.290

Gnomad4 OTH

AF:

0.244

Alfa

AF:

0.273

Hom.:

6048

Bravo

AF:

0.244

Asia WGS

AF:

0.168

AC:

584

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 425/2178=19.5% -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

DANN

Benign

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.70

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over