NM_018092.5:c.746A>G

Variant names:

• chr16-47109620-T-C
• rs766042295
• NM_018092.5:c.746A>G

Variant summary

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

The NM_018092.5(NETO2):​c.746A>G​(p.Glu249Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,614,052 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E249K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: NETO2 NM_018092.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92
• Publications: 0 publications found

Genes affected

NETO2 (HGNC:14644): (neuropilin and tolloid like 2) This gene encodes a predicted transmembrane protein containing two extracellular CUB domains followed by a low-density lipoprotein class A (LDLa) domain. A similar gene in rats encodes a protein that modulates glutamate signaling in the brain by regulating kainate receptor function. Expression of this gene may be a biomarker for proliferating infantile hemangiomas. A pseudogene of this gene is located on the long arm of chromosome 8. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

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=0.10478842).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018092.5. 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
	NETO2	NM_018092.5	MANE Select	c.746A>G	p.Glu249Gly	missense	Exon 7 of 9	NP_060562.3
	NETO2	NM_001201477.2		c.725A>G	p.Glu242Gly	missense	Exon 7 of 9	NP_001188406.1	Q8NC67-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NETO2	ENST00000562435.6	TSL:1 MANE Select	c.746A>G	p.Glu249Gly	missense	Exon 7 of 9	ENSP00000455169.1	Q8NC67-1
	NETO2	ENST00000303155.9	TSL:5	c.725A>G	p.Glu242Gly	missense	Exon 7 of 9	ENSP00000306726.5	Q8NC67-3
	NETO2	ENST00000878303.1		c.701A>G	p.Glu234Gly	missense	Exon 6 of 8	ENSP00000548362.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000215 AC: 54 AN: 251362 AF XY: 0.000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000923 AC: 135 AN: 1461838 Hom.: 0 Cov.: 30 AF XY: 0.0000908 AC XY: 66 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000179 AC: 8 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111984

Other (OTH) AF: 0.000199 AC: 12 AN: 60392

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000241 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000218

EpiControl AF: 0.000119

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	Uncertain	0.34
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.35
Sift	Benign	0.12	T
Sift4G	Uncertain	0.024	D
Polyphen		0.97	D
Vest4		0.74
MVP		0.49
MPC		0.50
ClinPred		0.25	T
GERP RS		5.5
PromoterAI		0.055	Neutral
Varity_R		0.37
gMVP		0.61
Mutation Taster		=8/92	disease causing

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: rs766042295; hg19: chr16-47143531;