2-70900694-T-G

Variant names:

• chr2-70900694-T-G
• NM_012476.3:c.73T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_012476.3(VAX2):​c.73T>G​(p.Cys25Gly) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VAX2 NM_012476.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.513
• Publications: 0 publications found

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]

ENSG00000296671 (HGNC:):

ACMG classification

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=0.16893387).
• BP6: Variant 2-70900694-T-G is Benign according to our data. Variant chr2-70900694-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2231484.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAX2	NM_012476.3	c.73T>G	p.Cys25Gly	missense_variant	Exon 1 of 3	ENST00000234392.3	NP_036608.1
VAX2	XM_011532750.4	c.73T>G	p.Cys25Gly	missense_variant	Exon 1 of 4		XP_011531052.1
VAX2	XM_011532751.4	c.73T>G	p.Cys25Gly	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	c.73T>G	p.Cys25Gly	missense_variant	Exon 1 of 3	1	NM_012476.3	ENSP00000234392.2
VAX2	ENST00000432367.6	n.-105T>G		upstream_gene_variant		5		ENSP00000405114.2
ENSG00000296671	ENST00000741094.1	n.-225A>C		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 18, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.8
DANN	Benign	0.55
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.18	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.51
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.22
Sift	Benign	0.68	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.076
MutPred		0.25		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.54
MPC		0.047
ClinPred		0.050	T
GERP RS		-2.3
PromoterAI		0.0036	Neutral
Varity_R		0.059
gMVP		0.12
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

hg19: chr2-71127824;