Genetic Variant CYP2C8:c.1149+49T>A (chr10-95042841-A-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.1149+49T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,526,176 control chromosomes in the GnomAD database, including 292,628 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 0.64 ( 31895 hom., cov: 32)

Exomes 𝑓: 0.61 ( 260733 hom. )

Consequence

CYP2C8
NM_000770.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.916

Publications

20 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=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000770.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CYP2C8	NM_000770.3	MANE Select	c.1149+49T>A	intron	N/A	NP_000761.3	P10632-1
CYP2C8	NM_001198853.1		c.939+49T>A	intron	N/A	NP_001185782.1	P10632
CYP2C8	NM_001198855.1		c.939+49T>A	intron	N/A	NP_001185784.1	P10632

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CYP2C8	ENST00000371270.6	TSL:1 MANE Select	c.1149+49T>A	intron	N/A	ENSP00000360317.3	P10632-1
CYP2C8	ENST00000854622.1		c.1230+49T>A	intron	N/A	ENSP00000524681.1
CYP2C8	ENST00000854631.1		c.1185+49T>A	intron	N/A	ENSP00000524690.1

Frequencies

GnomAD3 genomes

AF:

0.640

AC:

97325

AN:

151996

Hom.:

31854

Cov.:

show subpopulations

Gnomad AFR

AF:

0.758

Gnomad AMI

AF:

0.735

Gnomad AMR

AF:

0.502

Gnomad ASJ

AF:

0.648

Gnomad EAS

AF:

0.431

Gnomad SAS

AF:

0.616

Gnomad FIN

AF:

0.582

Gnomad MID

AF:

0.739

Gnomad NFE

AF:

0.624

Gnomad OTH

AF:

0.652

GnomAD2 exomes

AF:

0.578

AC:

144177

AN:

249452

AF XY:

0.587

show subpopulations

Gnomad AFR exome

AF:

0.760

Gnomad AMR exome

AF:

0.366

Gnomad ASJ exome

AF:

0.667

Gnomad EAS exome

AF:

0.426

Gnomad FIN exome

AF:

0.589

Gnomad NFE exome

AF:

0.618

Gnomad OTH exome

AF:

0.604

GnomAD4 exome

AF:

0.612

AC:

840900

AN:

1374060

Hom.:

260733

Cov.:

AF XY:

0.613

AC XY:

422428

AN XY:

688776

show subpopulations

African (AFR)

AF:

0.773

AC:

24493

AN:

31704

American (AMR)

AF:

0.385

AC:

17161

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.664

AC:

16973

AN:

25564

East Asian (EAS)

AF:

0.453

AC:

17740

AN:

39200

South Asian (SAS)

AF:

0.622

AC:

52506

AN:

84392

European-Finnish (FIN)

AF:

0.584

AC:

31124

AN:

53316

Middle Eastern (MID)

AF:

0.687

AC:

3854

AN:

5610

European-Non Finnish (NFE)

AF:

0.621

AC:

641469

AN:

1032168

Other (OTH)

AF:

0.619

AC:

35580

AN:

57502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

16367

32734

49101

65468

81835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16672

33344

50016

66688

83360

<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:

0.640

AC:

97411

AN:

152116

Hom.:

31895

Cov.:

AF XY:

0.635

AC XY:

47168

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.758

AC:

31481

AN:

41514

American (AMR)

AF:

0.501

AC:

7660

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.648

AC:

2248

AN:

3470

East Asian (EAS)

AF:

0.430

AC:

2227

AN:

5174

South Asian (SAS)

AF:

0.617

AC:

2976

AN:

4824

European-Finnish (FIN)

AF:

0.582

AC:

6148

AN:

10560

Middle Eastern (MID)

AF:

0.736

AC:

215

AN:

292

European-Non Finnish (NFE)

AF:

0.624

AC:

42410

AN:

67976

Other (OTH)

AF:

0.654

AC:

1376

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1763

3526

5288

7051

8814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.574

Hom.:

3195

Bravo

AF:

0.637

Asia WGS

AF:

0.561

AC:

1950

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.028

(source)

DANN

Benign

0.75

PhyloP100

-0.92

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over