Genetic Variant ENOX2:c.1129+6G>A (chrX-130656575-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006375.4(ENOX2):c.1129+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,032,789 control chromosomes in the GnomAD database, including 72 homozygotes. There are 3,574 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 4 hom., 249 hem., cov: 24)

Exomes 𝑓: 0.013 ( 68 hom. 3325 hem. )

Consequence

ENOX2
NM_006375.4 splice_region, intron

Scores

Splicing: ADA: 0.0004812

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.439

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant X-130656575-C-T is Benign according to our data. Variant chrX-130656575-C-T is described in ClinVar as [Benign]. Clinvar id is 789254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-130656575-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0129 (11875/920381) while in subpopulation NFE AF= 0.0159 (10899/685912). AF 95% confidence interval is 0.0156. There are 68 homozygotes in gnomad4_exome. There are 3325 alleles in male gnomad4_exome subpopulation. Median coverage is 16. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENOX2	NM_006375.4 link	c.1129+6G>A		splice_region_variant, intron_variant	Intron 10 of 14	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.1129+6G>A		splice_region_variant, intron_variant	Intron 10 of 14	2	NM_006375.4	ENSP00000377890.1		Q16206-2

Frequencies

GnomAD3 genomes

AF:

0.00874

AC:

982

AN:

112356

Hom.:

Cov.:

AF XY:

0.00724

AC XY:

250

AN XY:

34520

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00816

Gnomad ASJ

AF:

0.00414

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00112

Gnomad FIN

AF:

0.00262

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.00933

GnomAD3 exomes

AF:

0.00840

AC:

1427

AN:

169902

Hom.:

AF XY:

0.00855

AC XY:

492

AN XY:

57548

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.00615

Gnomad ASJ exome

AF:

0.00512

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00210

Gnomad FIN exome

AF:

0.00350

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.00745

GnomAD4 exome

AF:

0.0129

AC:

11875

AN:

920381

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

3325

AN XY:

265109

show subpopulations

Gnomad4 AFR exome

AF:

0.00159

Gnomad4 AMR exome

AF:

0.00568

Gnomad4 ASJ exome

AF:

0.00664

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00269

Gnomad4 FIN exome

AF:

0.00307

Gnomad4 NFE exome

AF:

0.0159

Gnomad4 OTH exome

AF:

0.00920

GnomAD4 genome

AF:

0.00872

AC:

980

AN:

112408

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

249

AN XY:

34582

show subpopulations

Gnomad4 AFR

AF:

0.00190

Gnomad4 AMR

AF:

0.00815

Gnomad4 ASJ

AF:

0.00414

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00112

Gnomad4 FIN

AF:

0.00262

Gnomad4 NFE

AF:

0.0148

Gnomad4 OTH

AF:

0.00921

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00800

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 03, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00048

dbscSNV1_RF

Benign

0.084

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