dbSNP rs6413419: CYP2E1:p.Val179Ile (chr10-133532171-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000773.4(CYP2E1):c.535G>A(p.Val179Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,613,682 control chromosomes in the GnomAD database, including 2,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.073 ( 936 hom., cov: 33)

Exomes 𝑓: 0.025 ( 1131 hom. )

Consequence

CYP2E1
NM_000773.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59

Publications

41 publications found

Variant links:

Genes affected

CYP2E1 (HGNC:2631): (cytochrome P450 family 2 subfamily E member 1) 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 is induced by ethanol, the diabetic state, and starvation. The enzyme metabolizes both endogenous substrates, such as ethanol, acetone, and acetal, as well as exogenous substrates including benzene, carbon tetrachloride, ethylene glycol, and nitrosamines which are premutagens found in cigarette smoke. Due to its many substrates, this enzyme may be involved in such varied processes as gluconeogenesis, hepatic cirrhosis, diabetes, and cancer. [provided by RefSeq, Jul 2008]

CYP2E1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0023357868).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2E1	NM_000773.4 link	c.535G>A	p.Val179Ile	missense_variant	Exon 4 of 9	ENST00000252945.8	NP_000764.1	P05181

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2E1	ENST00000252945.8 link	c.535G>A	p.Val179Ile	missense_variant	Exon 4 of 9	1	NM_000773.4	ENSP00000252945.3		P05181

Frequencies

GnomAD3 genomes

AF:

0.0730

AC:

11083

AN:

151894

Hom.:

936

Cov.:

show subpopulations

Gnomad AFR

AF:

0.202

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0411

Gnomad ASJ

AF:

0.0334

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0154

Gnomad FIN

AF:

0.0283

Gnomad MID

AF:

0.0573

Gnomad NFE

AF:

0.0218

Gnomad OTH

AF:

0.0635

GnomAD2 exomes

AF:

0.0336

AC:

8460

AN:

251432

AF XY:

0.0304

show subpopulations

Gnomad AFR exome

AF:

0.205

Gnomad AMR exome

AF:

0.0241

Gnomad ASJ exome

AF:

0.0335

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0277

Gnomad NFE exome

AF:

0.0224

Gnomad OTH exome

AF:

0.0359

GnomAD4 exome

AF:

0.0249

AC:

36442

AN:

1461670

Hom.:

1131

Cov.:

AF XY:

0.0245

AC XY:

17803

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.206

AC:

6878

AN:

33438

American (AMR)

AF:

0.0264

AC:

1180

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0354

AC:

924

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0196

AC:

1694

AN:

86252

European-Finnish (FIN)

AF:

0.0260

AC:

1385

AN:

53354

Middle Eastern (MID)

AF:

0.0569

AC:

328

AN:

5768

European-Non Finnish (NFE)

AF:

0.0198

AC:

21978

AN:

1111912

Other (OTH)

AF:

0.0343

AC:

2074

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1710

3421

5131

6842

8552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.0729

AC:

11086

AN:

152012

Hom.:

936

Cov.:

AF XY:

0.0717

AC XY:

5331

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.201

AC:

8320

AN:

41374

American (AMR)

AF:

0.0409

AC:

626

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0334

AC:

116

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.0158

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0283

AC:

300

AN:

10602

Middle Eastern (MID)

AF:

0.0582

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0218

AC:

1484

AN:

67994

Other (OTH)

AF:

0.0629

AC:

132

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

435

870

1305

1740

2175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0385

Hom.:

1406

Bravo

AF:

0.0815

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.205

AC:

905

ESP6500EA

AF:

0.0256

AC:

220

ExAC

AF:

0.0364

AC:

4413

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0255

EpiControl

AF:

0.0267

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

T;T;T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.81

.;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;L;.;.

PhyloP100

1.6

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.90

N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.20

T;T;T;T

Sift4G

Benign

0.42

T;T;T;T

Polyphen

1.0

D;D;.;.

Vest4

0.021

MPC

0.92

ClinPred

0.013

GERP RS

4.6

Varity_R

0.25

gMVP

0.43

Mutation Taster

=92/8

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