X-130670019-G-C

Variant names:

• chrX-130670019-G-C
• rs369982515
• NM_006375.4:c.640C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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. 12/20 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.68
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12734064).
• BS2: High Hemizygotes in GnomAd4 at 6 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006375.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENOX2	NM_006375.4	MANE Select	c.640C>G	p.Pro214Ala	missense	Exon 7 of 15	NP_006366.2
	ENOX2	NM_001382518.1		c.916C>G	p.Pro306Ala	missense	Exon 8 of 16	NP_001369447.1	A0A8I5KRI1
	ENOX2	NM_001382516.1		c.727C>G	p.Pro243Ala	missense	Exon 10 of 18	NP_001369445.1	Q16206-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENOX2	ENST00000394363.6	TSL:2 MANE Select	c.640C>G	p.Pro214Ala	missense	Exon 7 of 15	ENSP00000377890.1	Q16206-2
	ENOX2	ENST00000370927.5	TSL:1	c.727C>G	p.Pro243Ala	missense	Exon 5 of 13	ENSP00000359965.1	Q16206-1
	ENOX2	ENST00000432489.5	TSL:1	c.640C>G	p.Pro214Ala	missense	Exon 7 of 10	ENSP00000400304.1	B1AKF7

Frequencies

GnomAD3 genomes AF: 0.000214 AC: 24 AN: 112152 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.0000926 AC: 17 AN: 183496 AF XY: 0.0000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000492 AC: 54 AN: 1097440 Hom.: 0 Cov.: 30 AF XY: 0.0000441 AC XY: 16 AN XY: 362798

African (AFR) AF: 0.00 AC: 0 AN: 26391

American (AMR) AF: 0.000540 AC: 19 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000321 AC: 27 AN: 841404

Other (OTH) AF: 0.000174 AC: 8 AN: 46066

GnomAD4 genome AF: 0.000214 AC: 24 AN: 112208 Hom.: 0 Cov.: 23 AF XY: 0.000174 AC XY: 6 AN XY: 34386

African (AFR) AF: 0.0000647 AC: 2 AN: 30898

American (AMR) AF: 0.00178 AC: 19 AN: 10693

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53202

Other (OTH) AF: 0.000652 AC: 1 AN: 1534

Alfa AF: 0.000216 Hom.: 2

Bravo AF: 0.000416

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.093
Sift	Benign	0.23	T
Sift4G	Benign	0.13	T
Polyphen		0.034	B
Vest4		0.24
MVP		0.77
MPC		0.17
ClinPred		0.073	T
GERP RS		3.5
Varity_R		0.33
gMVP		0.59
Mutation Taster		=94/6	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: rs369982515; hg19: chrX-129803993;