chr2-70921139-C-A

Position:

• chr2-70921139-C-A

Variant summary

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

The NM_012476.3(VAX2):​c.289C>A​(p.Leu97Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAX2 NM_012476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.111

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAX2	NM_012476.3	c.289C>A	p.Leu97Met	missense_variant	2/3	ENST00000234392.3
VAX2	XM_011532750.4	c.289C>A	p.Leu97Met	missense_variant	2/4
VAX2	XM_011532751.4	c.289C>A	p.Leu97Met	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAX2	ENST00000234392.3	c.289C>A	p.Leu97Met	missense_variant	2/3	1	NM_012476.3	P1
VAX2	ENST00000432367.6	c.115C>A	p.Leu39Met	missense_variant, NMD_transcript_variant	2/15	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jun 06, 2023

The c.289C>A (p.L97M) alteration is located in exon 2 (coding exon 2) of the VAX2 gene. This alteration results from a C to A substitution at nucleotide position 289, causing the leucine (L) at amino acid position 97 to be replaced by a methionine (M). 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	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.034
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.097	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.39		Gain of methylation at K95 (P = 0.0624);
MVP		1.0
MPC		0.29
ClinPred		0.85	D
GERP RS		2.3
Varity_R		0.33
gMVP		0.23

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-71148269;