Genetic Variant ENOX2:p.Pro214Ala (chrX-130670019-G-C) – 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.640C>G(p.Pro214Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000645 in 1,209,648 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000049 ( 0 hom. 16 hem. )

Consequence

ENOX2
NM_006375.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.68

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=0.12734064).

BS2

High Hemizygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENOX2	NM_006375.4 link	c.640C>G	p.Pro214Ala	missense_variant	Exon 7 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.640C>G	p.Pro214Ala	missense_variant	Exon 7 of 15	2	NM_006375.4	ENSP00000377890.1		Q16206-2

Frequencies

GnomAD3 genomes

AF:

0.000214

AC:

AN:

112152

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34320

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00178

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:

0.0000376

Gnomad OTH

AF:

0.000661

GnomAD3 exomes

AF:

0.0000926

AC:

AN:

183496

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

67932

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000401

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:

0.0000488

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000492

AC:

AN:

1097440

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

362798

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000540

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000321

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000214

AC:

AN:

112208

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

34386

show subpopulations

Gnomad4 AFR

AF:

0.0000647

Gnomad4 AMR

AF:

0.00178

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.000652

Alfa

AF:

0.000216

Hom.:

Bravo

AF:

0.000416

ESP6500AA

AF:

0.000261

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

Mar 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.727C>G (p.P243A) alteration is located in exon 8 (coding exon 5) of the ENOX2 gene. This alteration results from a C to G substitution at nucleotide position 727, causing the proline (P) at amino acid position 243 to be replaced by an alanine (A). 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

Benign

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.66

.;D;D;.;T

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

.;.;D;D;D

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;L;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.5

D;D;D;D;D

REVEL

Benign

0.093

Sift

Benign

0.23

T;T;T;T;T

Sift4G

Benign

0.13

T;T;T;T;.

Polyphen

0.034

.;B;B;.;.

Vest4

0.24

MVP

0.77

MPC

0.17

ClinPred

0.073

GERP RS

3.5

Varity_R

0.33

gMVP

0.59

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