chr2-70933022-C-G

Position:

• chr2-70933022-C-G

Variant summary

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

The NM_012476.3(VAX2):​c.691C>G​(p.Pro231Ala) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P231L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: VAX2 NM_012476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13317865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAX2	NM_012476.3	c.691C>G	p.Pro231Ala	missense_variant	3/3	ENST00000234392.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAX2	ENST00000234392.3	c.691C>G	p.Pro231Ala	missense_variant	3/3	1	NM_012476.3	P1
VAX2	ENST00000432367.6	c.*45+8684C>G		intron_variant, NMD_transcript_variant		5
VAX2	ENST00000646783.1	c.80-6396C>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

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 07, 2023

The c.691C>G (p.P231A) alteration is located in exon 3 (coding exon 3) of the VAX2 gene. This alteration results from a C to G substitution at nucleotide position 691, causing the proline (P) at amino acid position 231 to be replaced by an alanine (A). 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	0.062
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.77	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.15
Sift	Uncertain	0.013	D
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.27		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.96
MPC		0.040
ClinPred		0.15	T
GERP RS		4.1
Varity_R		0.060
gMVP		0.30

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: chr2-71160152;