NM_000773.4:c.1165G>A

Variant names:

• chr10-133537760-G-A
• rs55897648
• NM_000773.4:c.1165G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000773.4(CYP2E1):​c.1165G>A​(p.Val389Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,613,374 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (10 hom.)
• Consequence: CYP2E1 NM_000773.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 26 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035592318).
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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.1165G>A	p.Val389Ile	missense	Exon 8 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.1165G>A	p.Val389Ile	missense	Exon 8 of 9	ENSP00000252945.3
	CYP2E1	ENST00000421586.5	TSL:1	c.904G>A	p.Val302Ile	missense	Exon 7 of 8	ENSP00000412754.1
	CYP2E1	ENST00000418356.1	TSL:1	c.754G>A	p.Val252Ile	missense	Exon 6 of 7	ENSP00000397299.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152122 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00209 AC: 525 AN: 250976 AF XY: 0.00203

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00851

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00266 AC: 3890 AN: 1461134 Hom.: 10 Cov.: 31 AF XY: 0.00259 AC XY: 1883 AN XY: 726858

African (AFR) AF: 0.000299 AC: 10 AN: 33452

American (AMR) AF: 0.000627 AC: 28 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00192 AC: 50 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000650 AC: 56 AN: 86152

European-Finnish (FIN) AF: 0.00832 AC: 444 AN: 53392

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.00284 AC: 3157 AN: 1111554

Other (OTH) AF: 0.00229 AC: 138 AN: 60364

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152240 Hom.: 1 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74442

African (AFR) AF: 0.000361 AC: 15 AN: 41518

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0108 AC: 114 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00197 Hom.: 3

Bravo AF: 0.00141

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00172 AC: 209

EpiCase AF: 0.00186

EpiControl AF: 0.00219

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.013
DANN	Benign	0.30
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.95	L
PhyloP100		-1.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.0080
Sift	Benign	0.64	T
Sift4G	Benign	0.59	T
Polyphen		0.0030	B
Vest4		0.087
MVP		0.26
MPC		0.25
ClinPred		0.00047	T
GERP RS		-8.6
Varity_R		0.042
gMVP		0.23
Mutation Taster		=95/5	polymorphism

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: rs55897648; hg19: chr10-135351264; COSMIC: COSV53315775; COSMIC: COSV53315775;