rs4646976

Variant names:

• chr10-133534223-A-G
• rs4646976
• NM_000773.4:c.967+326A>G

Variant summary

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

The NM_000773.4(CYP2E1):​c.967+326A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 152,262 control chromosomes in the GnomAD database, including 198 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 0.037 (198 hom., cov: 33)
• Consequence: CYP2E1 NM_000773.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.840
• Publications: 5 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 (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2E1	NM_000773.4	c.967+326A>G		intron_variant	Intron 6 of 8	ENST00000252945.8	NP_000764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2E1	ENST00000252945.8	c.967+326A>G		intron_variant	Intron 6 of 8	1	NM_000773.4	ENSP00000252945.3

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5609 AN: 152144 Hom.: 201 Cov.: 33

Gnomad AFR AF: 0.0593

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0634

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.0758

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00835

Gnomad OTH AF: 0.0377

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0367 AC: 5595 AN: 152262 Hom.: 198 Cov.: 33 AF XY: 0.0387 AC XY: 2883 AN XY: 74458

African (AFR) AF: 0.0591 AC: 2454 AN: 41532

American (AMR) AF: 0.0634 AC: 969 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3466

East Asian (EAS) AF: 0.177 AC: 918 AN: 5186

South Asian (SAS) AF: 0.0746 AC: 360 AN: 4824

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00834 AC: 567 AN: 68018

Other (OTH) AF: 0.0373 AC: 79 AN: 2116

Alfa AF: 0.0192 Hom.: 109

Bravo AF: 0.0415

Asia WGS AF: 0.124 AC: 431 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.97
DANN	Benign	0.54
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4646976; hg19: chr10-135347727;