Genetic Variant ENOX2:p.Arg273His (chrX-130667619-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006375.4(ENOX2):c.818G>A(p.Arg273His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,209,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 8 hem., cov: 22)

Exomes 𝑓: 0.000033 ( 0 hom. 5 hem. )

Consequence

ENOX2
NM_006375.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

ENOX2 (HGNC:2259): (ecto-NOX disulfide-thiol exchanger 2) This gene is a tumor-specific member of the ECTO-NOX family of genes that encode cell surface NADH oxidases. The encoded protein has two enzymatic activities: catalysis of hydroquinone or NADH oxidation, and protein disulfide interchange. The protein also displays prion-like properties. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ENOX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23837164).

BS2

High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENOX2	NM_006375.4 link	c.818G>A	p.Arg273His	missense_variant	Exon 8 of 15	ENST00000394363.6	NP_006366.2	Q16206-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENOX2	ENST00000394363.6 link	c.818G>A	p.Arg273His	missense_variant	Exon 8 of 15	2	NM_006375.4	ENSP00000377890.1		Q16206-2

Frequencies

GnomAD3 genomes

AF:

0.000205

AC:

AN:

111948

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

AN XY:

34118

show subpopulations

Gnomad AFR

AF:

0.000715

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000668

GnomAD3 exomes

AF:

0.0000763

AC:

AN:

183490

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67924

show subpopulations

Gnomad AFR exome

AF:

0.00106

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1097794

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363154

show subpopulations

Gnomad4 AFR exome

AF:

0.00110

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.000205

AC:

AN:

111948

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

AN XY:

34118

show subpopulations

Gnomad4 AFR

AF:

0.000715

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000668

Alfa

AF:

0.0000178

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.905G>A (p.R302H) alteration is located in exon 9 (coding exon 6) of the ENOX2 gene. This alteration results from a G to A substitution at nucleotide position 905, causing the arginine (R) at amino acid position 302 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

.;D;D;.;T

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;.;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.24

T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.2

.;M;M;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.5

D;D;D;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.028

D;D;D;D;D

Sift4G

Uncertain

0.025

D;D;D;D;.

Polyphen

1.0

.;D;D;.;.

Vest4

0.89

MVP

0.83

MPC

0.79

ClinPred

0.52

GERP RS

5.2

Varity_R

0.45

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over