11-19880042-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145117.5(NAV2):c.685G>T(p.Val229Leu) 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. 15/21 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: NAV2 NM_145117.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

Genes affected

NAV2 (HGNC:15997): (neuron navigator 2) This gene encodes a member of the neuron navigator gene family, which may play a role in cellular growth and migration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13688695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAV2	NM_145117.5	c.685G>T	p.Val229Leu	missense_variant	5/38	ENST00000349880.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAV2	ENST00000349880.9	c.685G>T	p.Val229Leu	missense_variant	5/38	1	NM_145117.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Jan 04, 2024

The c.685G>T (p.V229L) alteration is located in exon 5 (coding exon 5) of the NAV2 gene. This alteration results from a G to T substitution at nucleotide position 685, causing the valine (V) at amino acid position 229 to be replaced by a leucine (L). 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	Benign	0.090
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	20
Dann	Benign	0.94
Eigen	Benign	-0.13
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;T;T;D;T;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.76	D;N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.0	N;N;.;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.14	T;T;.;.;T;T
Sift4G	Benign	0.64	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;B;.
Vest4		0.32
MutPred		0.087		.;Loss of phosphorylation at T232 (P = 0.1634);Loss of phosphorylation at T232 (P = 0.1634);Loss of phosphorylation at T232 (P = 0.1634);Loss of phosphorylation at T232 (P = 0.1634);Loss of phosphorylation at T232 (P = 0.1634);
MVP		0.19
MPC		0.15
ClinPred		0.51	D
GERP RS		5.7
Varity_R		0.031
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs770201436; hg19: chr11-19901588;