16-47122664-T-A

Position:

• chr16-47122664-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018092.5(NETO2):​c.647A>T​(p.Lys216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NETO2 NM_018092.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26870936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NETO2	NM_018092.5	c.647A>T	p.Lys216Ile	missense_variant	6/9	ENST00000562435.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NETO2	ENST00000562435.6	c.647A>T	p.Lys216Ile	missense_variant	6/9	1	NM_018092.5	P4
NETO2	ENST00000303155.9	c.626A>T	p.Lys209Ile	missense_variant	6/9	5		A1
NETO2	ENST00000562559.5	c.281A>T	p.Lys94Ile	missense_variant	3/5	3
NETO2	ENST00000563078.1	c.158A>T	p.Lys53Ile	missense_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.647A>T (p.K216I) alteration is located in exon 6 (coding exon 6) of the NETO2 gene. This alteration results from a A to T substitution at nucleotide position 647, causing the lysine (K) at amino acid position 216 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.16
Sift	Benign	0.054	T;T
Sift4G	Uncertain	0.052	T;T
Polyphen		0.096	B;.
Vest4		0.45
MutPred		0.59		Loss of methylation at K216 (P = 0.0188);.;
MVP		0.34
MPC		0.68
ClinPred		0.62	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-47156575;