X-130670019-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006375.4(ENOX2):​c.640C>T​(p.Pro214Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,097,440 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P214A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: ENOX2 NM_006375.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42276436).

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>T	p.Pro214Ser	missense	Exon 7 of 15	NP_006366.2
	ENOX2	NM_001382518.1		c.916C>T	p.Pro306Ser	missense	Exon 8 of 16	NP_001369447.1	A0A8I5KRI1
	ENOX2	NM_001382516.1		c.727C>T	p.Pro243Ser	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>T	p.Pro214Ser	missense	Exon 7 of 15	ENSP00000377890.1	Q16206-2
	ENOX2	ENST00000370927.5	TSL:1	c.727C>T	p.Pro243Ser	missense	Exon 5 of 13	ENSP00000359965.1	Q16206-1
	ENOX2	ENST00000432489.5	TSL:1	c.640C>T	p.Pro214Ser	missense	Exon 7 of 10	ENSP00000400304.1	B1AKF7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097440 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362798

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

American (AMR) AF: 0.00 AC: 0 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: 0.00000357 AC: 3 AN: 841404

Other (OTH) AF: 0.00 AC: 0 AN: 46066

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.27
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.018	D
Polyphen		0.95	P
Vest4		0.48
MutPred		0.27		Gain of phosphorylation at P243 (P = 0.015)
MVP		0.77
MPC		0.36
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.49
gMVP		0.69
Mutation Taster		=77/23	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; COSMIC: COSV57658030; COSMIC: COSV57658030;