Genetic Variant VAX2:p.Gly66Arg (chr2-70900817-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012476.3(VAX2):c.196G>C(p.Gly66Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000225 in 1,332,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

VAX2
NM_012476.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0600

Variant links:

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]

VAX2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05795452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAX2	NM_012476.3 link	c.196G>C	p.Gly66Arg	missense_variant	Exon 1 of 3	ENST00000234392.3	NP_036608.1	Q9UIW0F1T0K5
VAX2	XM_011532750.4 link	c.196G>C	p.Gly66Arg	missense_variant	Exon 1 of 4		XP_011531052.1
VAX2	XM_011532751.4 link	c.196G>C	p.Gly66Arg	missense_variant	Exon 1 of 4		XP_011531053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAX2	ENST00000234392.3 link	c.196G>C	p.Gly66Arg	missense_variant	Exon 1 of 3	1	NM_012476.3	ENSP00000234392.2		Q9UIW0
VAX2	ENST00000432367.6 link	n.19G>C		non_coding_transcript_exon_variant	Exon 1 of 15	5		ENSP00000405114.2		C9J5E3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000225

AC:

AN:

1332494

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

656178

show subpopulations

African (AFR)

AF:

0.0000360

AC:

AN:

27780

American (AMR)

AF:

0.00

AC:

AN:

29306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23444

East Asian (EAS)

AF:

0.00

AC:

AN:

30412

South Asian (SAS)

AF:

0.00

AC:

AN:

72624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3924

European-Non Finnish (NFE)

AF:

0.00000191

AC:

AN:

1049812

Other (OTH)

AF:

0.00

AC:

AN:

55084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.196G>C (p.G66R) alteration is located in exon 1 (coding exon 1) of the VAX2 gene. This alteration results from a G to C substitution at nucleotide position 196, causing the glycine (G) at amino acid position 66 to be replaced by an arginine (R). 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

0.095

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.056

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.4

PhyloP100

0.060

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.65

REVEL

Benign

0.12

Sift

Benign

0.62

Sift4G

Benign

0.47

Polyphen

0.0070

Vest4

0.054

MutPred

0.22

Loss of catalytic residue at G66 (P = 0.129);

MVP

0.92

MPC

0.046

ClinPred

0.16

GERP RS

0.96

PromoterAI

0.041

Neutral

(source)

Varity_R

0.086

gMVP

0.14

Mutation Taster

=96/4

polymorphism

(source)

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

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2-70900817-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over