10-95042980-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_000770.3(CYP2C8):c.1059C>T(p.His353=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00553 in 1,614,018 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (191 hom.)
• Consequence: CYP2C8 NM_000770.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.775

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 10-95042980-G-A is Benign according to our data. Variant chr10-95042980-G-A is described in ClinVar as [Benign]. Clinvar id is 775289.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-95042980-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.775 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0037 (564/152270) while in subpopulation SAS AF= 0.0498 (240/4822). AF 95% confidence interval is 0.0446. There are 11 homozygotes in gnomad4. There are 332 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C8	NM_000770.3	c.1059C>T	p.His353=	synonymous_variant	7/9	ENST00000371270.6
CYP2C8	NM_001198853.1	c.849C>T	p.His283=	synonymous_variant	7/9
CYP2C8	NM_001198855.1	c.849C>T	p.His283=	synonymous_variant	8/10
CYP2C8	NM_001198854.1	c.753C>T	p.His251=	synonymous_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C8	ENST00000371270.6	c.1059C>T	p.His353=	synonymous_variant	7/9	1	NM_000770.3	P1

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 562 AN: 152152 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0493

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00882 AC: 2217 AN: 251478 Hom.: 67 AF XY: 0.0113 AC XY: 1541 AN XY: 135914

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0506

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00323

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00572 AC: 8355 AN: 1461748 Hom.: 191 Cov.: 32 AF XY: 0.00734 AC XY: 5334 AN XY: 727176

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0502

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00254

Gnomad4 OTH exome AF: 0.00782

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152270 Hom.: 11 Cov.: 32 AF XY: 0.00446 AC XY: 332 AN XY: 74442

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0498

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00450 Hom.: 14

Bravo AF: 0.00254

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00480

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.10
Dann	Benign	0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11188150; hg19: chr10-96802737; COSMIC: COSV104428898; COSMIC: COSV104428898;