rs2275622

Variant names:

• chr10-95067421-T-C
• rs2275622
• NM_000770.3:c.332-64A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000770.3(CYP2C8):​c.332-64A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,613,048 control chromosomes in the GnomAD database, including 350,542 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (36768 hom., cov: 33)
  • Exomes 𝑓: 0.65 (313774 hom.)
• Consequence: CYP2C8 NM_000770.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.42
• Publications: 20 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.615978E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C8	NM_000770.3	c.332-64A>G		intron_variant	Intron 2 of 8	ENST00000371270.6	NP_000761.3
CYP2C8	NM_001198853.1	c.122-64A>G		intron_variant	Intron 2 of 8		NP_001185782.1
CYP2C8	NM_001198855.1	c.122-64A>G		intron_variant	Intron 3 of 9		NP_001185784.1
CYP2C8	NM_001198854.1	c.26-64A>G		intron_variant	Intron 1 of 7		NP_001185783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6	c.332-64A>G		intron_variant	Intron 2 of 8	1	NM_000770.3	ENSP00000360317.3

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104495 AN: 152002 Hom.: 36709 Cov.: 33

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.737

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.705

GnomAD2 exomes AF: 0.618 AC: 154421 AN: 249722 AF XY: 0.629

Gnomad AFR exome AF: 0.818

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.720

Gnomad EAS exome AF: 0.455

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.654

GnomAD4 exome AF: 0.651 AC: 951593 AN: 1460928 Hom.: 313774 Cov.: 38 AF XY: 0.653 AC XY: 474916 AN XY: 726828

African (AFR) AF: 0.830 AC: 27759 AN: 33446

American (AMR) AF: 0.421 AC: 18789 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 18721 AN: 26134

East Asian (EAS) AF: 0.471 AC: 18692 AN: 39688

South Asian (SAS) AF: 0.669 AC: 57717 AN: 86240

European-Finnish (FIN) AF: 0.598 AC: 31920 AN: 53400

Middle Eastern (MID) AF: 0.782 AC: 4511 AN: 5766

European-Non Finnish (NFE) AF: 0.660 AC: 733221 AN: 1111264

Other (OTH) AF: 0.667 AC: 40263 AN: 60350

GnomAD4 genome AF: 0.688 AC: 104604 AN: 152120 Hom.: 36768 Cov.: 33 AF XY: 0.681 AC XY: 50650 AN XY: 74358

African (AFR) AF: 0.818 AC: 33968 AN: 41508

American (AMR) AF: 0.557 AC: 8503 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2451 AN: 3470

East Asian (EAS) AF: 0.461 AC: 2388 AN: 5176

South Asian (SAS) AF: 0.668 AC: 3224 AN: 4826

European-Finnish (FIN) AF: 0.596 AC: 6302 AN: 10576

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45355 AN: 67988

Other (OTH) AF: 0.706 AC: 1493 AN: 2114

Alfa AF: 0.673 Hom.: 97844

Bravo AF: 0.687

TwinsUK AF: 0.663 AC: 2459

ALSPAC AF: 0.650 AC: 2504

ExAC AF: 0.630 AC: 76501

Asia WGS AF: 0.607 AC: 2112 AN: 3478

EpiCase AF: 0.685

EpiControl AF: 0.690

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0040
DANN	Benign	0.052
Eigen	Benign	-2.8
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-0.95	T
PhyloP100		-3.4
Sift4G	Benign	1.0	T
Vest4		0.015
ClinPred		0.0011	T
GERP RS		-7.0
PromoterAI		-0.032	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs2275622; hg19: chr10-96827178; COSMIC: COSV64875985;