Genetic Variant ENOX2:p.Arg341His (chrX-130656688-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_006375.4(ENOX2):c.1022G>A(p.Arg341His) variant causes a missense change. The variant allele was found at a frequency of 0.000056 in 1,090,216 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 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 0.000045 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000057 ( 0 hom. 18 hem. )

Consequence

ENOX2
NM_006375.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.59

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27160817).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENOX2	NM_006375.4 link	c.1022G>A	p.Arg341His	missense_variant	Exon 10 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.1022G>A	p.Arg341His	missense_variant	Exon 10 of 15	2	NM_006375.4	ENSP00000377890.1		Q16206-2

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111790

Hom.:

Cov.:

AF XY:

0.0000882

AC XY:

AN XY:

34028

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000277

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

166785

Hom.:

AF XY:

0.0000362

AC XY:

AN XY:

55193

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000645

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000261

Gnomad OTH exome

AF:

0.000246

GnomAD4 exome

AF:

0.0000572

AC:

AN:

978371

Hom.:

Cov.:

AF XY:

0.0000651

AC XY:

AN XY:

276409

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000206

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000675

Gnomad4 OTH exome

AF:

0.000119

GnomAD4 genome

AF:

0.0000447

AC:

AN:

111845

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

34093

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000278

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1109G>A (p.R370H) alteration is located in exon 11 (coding exon 8) of the ENOX2 gene. This alteration results from a G to A substitution at nucleotide position 1109, causing the arginine (R) at amino acid position 370 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

Pathogenic

0.65

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

.;D;D;.;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

.;.;D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

2.0

.;M;M;.;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.5

D;D;D;D;.;D

REVEL

Benign

0.26

Sift

Uncertain

0.023

D;D;D;D;.;D

Sift4G

Uncertain

0.039

D;D;D;D;D;.

Polyphen

1.0

.;D;D;.;.;.

Vest4

0.38

MutPred

0.32

.;Loss of MoRF binding (P = 0.0315);Loss of MoRF binding (P = 0.0315);.;.;.;

MVP

0.86

MPC

0.32

ClinPred

0.73

GERP RS

4.1

Varity_R

0.56

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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