10-95068566-T-C

Variant names:

• chr10-95068566-T-C
• rs2071426
• NM_000770.3:c.168+669A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.32
• Publications: 23 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: Benign. The variant received -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04908947 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001198855.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C8	NM_000770.3	MANE Select	c.168+669A>G		intron	N/A	NP_000761.3	P10632-1
	CYP2C8	NM_001198853.1		c.-43+631A>G		intron	N/A	NP_001185782.1	P10632
	CYP2C8	NM_001198855.1		c.-43+1A>G		splice_donor intron	N/A	NP_001185784.1	P10632

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C8	ENST00000371270.6	TSL:1 MANE Select	c.168+669A>G		intron	N/A	ENSP00000360317.3	P10632-1
	CYP2C8	ENST00000854622.1		c.168+669A>G		intron	N/A	ENSP00000524681.1
	CYP2C8	ENST00000854631.1		c.168+669A>G		intron	N/A	ENSP00000524690.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38335 AN: 151974 Hom.: 5047 Cov.: 32

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.: 25 AF XY: 0.269 AC XY: 148953 AN XY: 552876

African (AFR) AF: 0.235 AC: 5684 AN: 24202

American (AMR) AF: 0.139 AC: 3919 AN: 28258

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 3852 AN: 15854

East Asian (EAS) AF: 0.0601 AC: 770 AN: 12818

South Asian (SAS) AF: 0.240 AC: 18231 AN: 75990

European-Finnish (FIN) AF: 0.271 AC: 3423 AN: 12640

Middle Eastern (MID) AF: 0.254 AC: 1113 AN: 4376

European-Non Finnish (NFE) AF: 0.281 AC: 256180 AN: 910432

Other (OTH) AF: 0.256 AC: 10551 AN: 41162

GnomAD4 genome AF: 0.252 AC: 38373 AN: 152092 Hom.: 5055 Cov.: 32 AF XY: 0.248 AC XY: 18437 AN XY: 74336

African (AFR) AF: 0.242 AC: 10023 AN: 41460

American (AMR) AF: 0.174 AC: 2654 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 851 AN: 3468

East Asian (EAS) AF: 0.0577 AC: 299 AN: 5182

South Asian (SAS) AF: 0.235 AC: 1131 AN: 4814

European-Finnish (FIN) AF: 0.264 AC: 2797 AN: 10576

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19735 AN: 67978

Other (OTH) AF: 0.244 AC: 516 AN: 2114

Alfa AF: 0.270 Hom.: 16194

Bravo AF: 0.244

Asia WGS AF: 0.168 AC: 584 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	21
DANN	Benign	0.57
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2071426; hg19: chr10-96828323; COSMIC: COSV64876380; COSMIC: COSV64876380;