X-130635067-A-G

Variant names:

• chrX-130635067-A-G
• NM_006375.4:c.1336T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006375.4(ENOX2):​c.1336T>C​(p.Tyr446His) variant causes a missense change. The variant allele was found at a frequency of 0.000000942 in 1,062,065 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: ENOX2 NM_006375.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24493682).

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.1336T>C	p.Tyr446His	missense	Exon 12 of 15	NP_006366.2
	ENOX2	NM_001382518.1		c.1612T>C	p.Tyr538His	missense	Exon 13 of 16	NP_001369447.1	A0A8I5KRI1
	ENOX2	NM_001382516.1		c.1423T>C	p.Tyr475His	missense	Exon 15 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.1336T>C	p.Tyr446His	missense	Exon 12 of 15	ENSP00000377890.1	Q16206-2
	ENOX2	ENST00000370927.5	TSL:1	c.1423T>C	p.Tyr475His	missense	Exon 10 of 13	ENSP00000359965.1	Q16206-1
	ENOX2	ENST00000686943.1		c.1612T>C	p.Tyr538His	missense	Exon 13 of 16	ENSP00000509235.1	A0A8I5KRI1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.42e-7 AC: 1 AN: 1062065 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 331865

African (AFR) AF: 0.00 AC: 0 AN: 25656

American (AMR) AF: 0.00 AC: 0 AN: 34501

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19042

East Asian (EAS) AF: 0.00 AC: 0 AN: 29968

South Asian (SAS) AF: 0.00 AC: 0 AN: 52298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4015

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 811405

Other (OTH) AF: 0.0000223 AC: 1 AN: 44894

GnomAD4 genome Cov.: 23

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	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.068
Sift	Benign	0.45	T
Sift4G	Benign	0.55	T
Polyphen		0.94	P
Vest4		0.44
MutPred		0.18		Loss of stability (P = 0.0419)
MVP		0.74
MPC		0.56
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.10
Mutation Taster		=93/7	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

hg19: chrX-129769041;