rs6413419

chr10-133532171-G-Achr10-133532171-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023357868).
• BP6: Variant 10-133532171-G-A is Benign according to our data. Variant chr10-133532171-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CYP2E1	NM_000773.4	c.535G>A	p.Val179Ile	missense_variant	4/9	ENST00000252945.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2E1	ENST00000252945.8	c.535G>A	p.Val179Ile	missense_variant	4/9	1	NM_000773.4	P1

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

GnomAD3 exomes AF: 0.0336 AC: 8460 AN: 251432 Hom.: 453 AF XY: 0.0304 AC XY: 4129 AN XY: 135894

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 SAS exome AF: 0.0191

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

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.0264

Gnomad4 ASJ exome AF: 0.0354

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0196

Gnomad4 FIN exome AF: 0.0260

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0343

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

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0158

Gnomad4 FIN AF: 0.0283

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0318 Hom.: 441

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 v4.3

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;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.85	D
MetaRNN	Benign	0.0023	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.;.
MutationTaster	Benign	0.50	P;P;P
PrimateAI	Benign	0.48	T
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	T
GERP RS		4.6
Varity_R		0.25
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs6413419; hg19: chr10-135345675;