chr2-70900835-G-A

Position:

• chr2-70900835-G-A

Variant summary

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

The NM_012476.3(VAX2):​c.214G>A​(p.Glu72Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000229 in 1,310,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: VAX2 NM_012476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

Genes affected

VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

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=0.32581466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAX2	NM_012476.3	c.214G>A	p.Glu72Lys	missense_variant	1/3	ENST00000234392.3
VAX2	XM_011532750.4	c.214G>A	p.Glu72Lys	missense_variant	1/4
VAX2	XM_011532751.4	c.214G>A	p.Glu72Lys	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAX2	ENST00000234392.3	c.214G>A	p.Glu72Lys	missense_variant	1/3	1	NM_012476.3	P1
VAX2	ENST00000432367.6	c.40G>A	p.Glu14Lys	missense_variant, NMD_transcript_variant	1/15	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000229 AC: 3 AN: 1310406 Hom.: 0 Cov.: 33 AF XY: 0.00000155 AC XY: 1 AN XY: 644200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000144

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Mar 19, 2024

The c.214G>A (p.E72K) alteration is located in exon 1 (coding exon 1) of the VAX2 gene. This alteration results from a G to A substitution at nucleotide position 214, causing the glutamic acid (E) at amino acid position 72 to be replaced by a lysine (K). 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	0.24
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.95	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.65	T
Polyphen		0.96	D
Vest4		0.23
MutPred		0.30		Gain of ubiquitination at E72 (P = 0.0048);
MVP		0.92
MPC		0.095
ClinPred		0.85	D
GERP RS		4.0
Varity_R		0.26
gMVP		0.26

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: rs1486035052; hg19: chr2-71127965;