Genetic Variant NM_000770.3:c.332-36G>A (chr10-95067393-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.332-36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,038 control chromosomes in the GnomAD database, including 916 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 0.044 ( 466 hom., cov: 33)

Exomes 𝑓: 0.0074 ( 450 hom. )

Consequence

CYP2C8
NM_000770.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.89

Publications

19 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 (MetaRNN=0.00172019).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 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.332-36G>A	intron	N/A	NP_000761.3	P10632-1
CYP2C8	NM_001198853.1		c.122-36G>A	intron	N/A	NP_001185782.1	P10632
CYP2C8	NM_001198855.1		c.122-36G>A	intron	N/A	NP_001185784.1	P10632

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP2C8	ENST00000371270.6	TSL:1 MANE Select	c.332-36G>A		intron	N/A	ENSP00000360317.3	P10632-1
CYP2C8	ENST00000628935.1	TSL:5	c.38G>A	p.Cys13Tyr	missense	Exon 1 of 6	ENSP00000487145.1	A0A0D9SG51
CYP2C8	ENST00000854622.1		c.332-36G>A		intron	N/A	ENSP00000524681.1

Frequencies

GnomAD3 genomes

AF:

0.0440

AC:

6695

AN:

152140

Hom.:

464

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0164

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0193

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00282

Gnomad OTH

AF:

0.0406

GnomAD2 exomes

AF:

0.0151

AC:

3777

AN:

250318

AF XY:

0.0132

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.00788

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00312

Gnomad OTH exome

AF:

0.00986

GnomAD4 exome

AF:

0.00736

AC:

10763

AN:

1461780

Hom.:

450

Cov.:

AF XY:

0.00734

AC XY:

5335

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.152

AC:

5073

AN:

33472

American (AMR)

AF:

0.00944

AC:

422

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

390

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39696

South Asian (SAS)

AF:

0.0203

AC:

1749

AN:

86252

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.0229

AC:

132

AN:

5766

European-Non Finnish (NFE)

AF:

0.00195

AC:

2172

AN:

1111972

Other (OTH)

AF:

0.0134

AC:

810

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

601

1202

1802

2403

3004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

208

416

624

832

1040

<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:

0.0441

AC:

6708

AN:

152258

Hom.:

466

Cov.:

AF XY:

0.0430

AC XY:

3205

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.145

AC:

6023

AN:

41524

American (AMR)

AF:

0.0164

AC:

250

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0193

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00282

AC:

192

AN:

68036

Other (OTH)

AF:

0.0402

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

299

598

897

1196

1495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0168

Hom.:

523

Bravo

AF:

0.0504

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.147

AC:

647

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.0184

AC:

2237

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.00387

EpiControl

AF:

0.00469

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.38

(source)

DANN

Benign

0.32

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

PhyloP100

-1.9

Sift4G

Benign

0.062

Vest4

0.015

ClinPred

0.00079

GERP RS

-0.87

PromoterAI

-0.018

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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