rs2275622

Positions:

• chr10-95067421-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Likely benign (no stars).

• 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

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.615978E-7).
• BP6: Variant 10-95067421-T-C is Benign according to our data. Variant chr10-95067421-T-C is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
CYP2C8	NM_000770.3	c.332-64A>G		intron_variant		ENST00000371270.6
CYP2C8	NM_001198853.1	c.122-64A>G		intron_variant
CYP2C8	NM_001198854.1	c.26-64A>G		intron_variant
CYP2C8	NM_001198855.1	c.122-64A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C8	ENST00000371270.6	c.332-64A>G		intron_variant		1	NM_000770.3	P1

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

GnomAD3 exomes AF: 0.618 AC: 154421 AN: 249722 Hom.: 49768 AF XY: 0.629 AC XY: 85130 AN XY: 135264

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 SAS exome AF: 0.673

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

Gnomad4 AFR exome AF: 0.830

Gnomad4 AMR exome AF: 0.421

Gnomad4 ASJ exome AF: 0.716

Gnomad4 EAS exome AF: 0.471

Gnomad4 SAS exome AF: 0.669

Gnomad4 FIN exome AF: 0.598

Gnomad4 NFE exome AF: 0.660

Gnomad4 OTH exome AF: 0.667

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

Gnomad4 AFR AF: 0.818

Gnomad4 AMR AF: 0.557

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.461

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.596

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.706

Alfa AF: 0.672 Hom.: 36235

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
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
MutationTaster	Benign	1.0	P;P;P
Sift4G	Benign	1.0	T
Vest4		0.015
ClinPred		0.0011	T
GERP RS		-7.0

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

Publications

LitVar

Other links and lift over

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