Genetic Variant NM_000770.3:c.1291+106G>A (chr10-95038791-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000770.3(CYP2C8):c.1291+106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,058,968 control chromosomes in the GnomAD database, including 27,445 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 0.24 ( 4972 hom., cov: 32)

Exomes 𝑓: 0.21 ( 22473 hom. )

Consequence

CYP2C8
NM_000770.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.70

Publications

53 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CYP2C8	NM_000770.3 link	c.1291+106G>A	intron_variant	Intron 8 of 8	ENST00000371270.6	NP_000761.3	P10632-1
CYP2C8	NM_001198853.1 link	c.1081+106G>A	intron_variant	Intron 8 of 8		NP_001185782.1	P10632B7Z1F5
CYP2C8	NM_001198855.1 link	c.1081+106G>A	intron_variant	Intron 9 of 9		NP_001185784.1	P10632B7Z1F5
CYP2C8	NM_001198854.1 link	c.985+106G>A	intron_variant	Intron 7 of 7		NP_001185783.1	P10632-2B7Z1F5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C8	ENST00000371270.6 link	c.1291+106G>A		intron_variant	Intron 8 of 8	1	NM_000770.3	ENSP00000360317.3		P10632-1

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36807

AN:

151918

Hom.:

4956

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.191

Gnomad AMR

AF:

0.175

Gnomad ASJ

AF:

0.210

Gnomad EAS

AF:

0.394

Gnomad SAS

AF:

0.333

Gnomad FIN

AF:

0.195

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.230

GnomAD4 exome

AF:

0.211

AC:

191536

AN:

906932

Hom.:

22473

AF XY:

0.216

AC XY:

101664

AN XY:

471698

show subpopulations

African (AFR)

AF:

0.354

AC:

7952

AN:

22466

American (AMR)

AF:

0.137

AC:

5288

AN:

38650

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

4677

AN:

22004

East Asian (EAS)

AF:

0.419

AC:

15029

AN:

35900

South Asian (SAS)

AF:

0.329

AC:

23526

AN:

71582

European-Finnish (FIN)

AF:

0.186

AC:

8600

AN:

46180

Middle Eastern (MID)

AF:

0.205

AC:

652

AN:

3178

European-Non Finnish (NFE)

AF:

0.187

AC:

116682

AN:

625120

Other (OTH)

AF:

0.218

AC:

9130

AN:

41852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

7960

15921

23881

31842

39802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3194

6388

9582

12776

15970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.242

AC:

36850

AN:

152036

Hom.:

4972

Cov.:

AF XY:

0.244

AC XY:

18168

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.346

AC:

14337

AN:

41446

American (AMR)

AF:

0.175

AC:

2679

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

730

AN:

3470

East Asian (EAS)

AF:

0.394

AC:

2032

AN:

5158

South Asian (SAS)

AF:

0.334

AC:

1609

AN:

4820

European-Finnish (FIN)

AF:

0.195

AC:

2062

AN:

10560

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.186

AC:

12672

AN:

67982

Other (OTH)

AF:

0.237

AC:

500

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1355

2711

4066

5422

6777

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.211

Hom.:

11692

Bravo

AF:

0.243

Asia WGS

AF:

0.364

AC:

1264

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.48

(source)

DANN

Benign

0.48

PhyloP100

-2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over