rs28969387

Variant names:

• chr10-133538852-A-G
• rs28969387
• NM_000773.4:c.1370A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-133538852-A-G
• chr10-133538852-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000773.4(CYP2E1):​c.1370A>G​(p.His457Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H457L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP2E1 NM_000773.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.44
• Publications: 12 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2E1	NM_000773.4	MANE Select	c.1370A>G	p.His457Arg	missense	Exon 9 of 9	NP_000764.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2E1	ENST00000252945.8	TSL:1 MANE Select	c.1370A>G	p.His457Arg	missense	Exon 9 of 9	ENSP00000252945.3
	CYP2E1	ENST00000368520.1	TSL:1	n.1358+960A>G		intron	N/A
	CYP2E1	ENST00000883804.1		c.1490A>G	p.His497Arg	missense	Exon 9 of 9	ENSP00000553863.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.78	N
PhyloP100		4.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.021	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.11
MutPred		0.61		Loss of methylation at K461 (P = 0.0513)
MVP		0.75
MPC		0.96
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.85
Mutation Taster		=33/67	disease causing

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: rs28969387; hg19: chr10-135352356;