10-133532171-G-A

Variant names:

• chr10-133532171-G-A
• rs6413419
• NM_000773.4:c.535G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• Publications: 41 publications found

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000773.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2E1	NM_000773.4	MANE Select	c.535G>A	p.Val179Ile	missense	Exon 4 of 9	NP_000764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2E1	ENST00000252945.8	TSL:1 MANE Select	c.535G>A	p.Val179Ile	missense	Exon 4 of 9	ENSP00000252945.3
	CYP2E1	ENST00000421586.5	TSL:1	c.274G>A	p.Val92Ile	missense	Exon 3 of 8	ENSP00000412754.1
	CYP2E1	ENST00000418356.1	TSL:1	c.124G>A	p.Val42Ile	missense	Exon 2 of 7	ENSP00000397299.1

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11083 AN: 151894 Hom.: 936 Cov.: 33

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

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.: 31 AF XY: 0.0245 AC XY: 17803 AN XY: 727126

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: 1 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

GnomAD4 genome AF: 0.0729 AC: 11086 AN: 152012 Hom.: 936 Cov.: 33 AF XY: 0.0717 AC XY: 5331 AN XY: 74314

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: 0 AN: 5162

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4816

European-Finnish (FIN) AF: 0.0283 AC: 300 AN: 10602

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.0218 AC: 1484 AN: 67994

Other (OTH) AF: 0.0629 AC: 132 AN: 2100

Alfa AF: 0.0385 Hom.: 1406

Bravo AF: 0.0815

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.205 AC: 905

ESP6500EA AF: 0.0256 AC: 220

ExAC AF: 0.0364 AC: 4413

Asia WGS AF: 0.0130 AC: 48 AN: 3478

EpiCase AF: 0.0255

EpiControl AF: 0.0267

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.10
Sift	Benign	0.20	T
Sift4G	Benign	0.42	T
Polyphen		1.0	D
Vest4		0.021
MPC		0.92
ClinPred		0.013	T
GERP RS		4.6
Varity_R		0.25
gMVP		0.43
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6413419; hg19: chr10-135345675;