NM_012476.3:c.70C>G

Variant names:

• chr2-70900691-C-G
• rs2234496
• NM_012476.3:c.70C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012476.3(VAX2):​c.70C>G​(p.Arg24Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,326,858 control chromosomes in the GnomAD database, including 41 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (32 hom., cov: 34)
  • Exomes 𝑓: 0.00081 (9 hom.)
• Consequence: VAX2 NM_012476.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.167
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019215941).
• BP6: Variant 2-70900691-C-G is Benign according to our data. Variant chr2-70900691-C-G is described in ClinVar as [Benign]. Clinvar id is 783331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00982 (1494/152166) while in subpopulation AFR AF = 0.034 (1414/41530). AF 95% confidence interval is 0.0326. There are 32 homozygotes in GnomAd4. There are 725 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAX2	NM_012476.3	c.70C>G	p.Arg24Gly	missense_variant	Exon 1 of 3	ENST00000234392.3	NP_036608.1
VAX2	XM_011532750.4	c.70C>G	p.Arg24Gly	missense_variant	Exon 1 of 4		XP_011531052.1
VAX2	XM_011532751.4	c.70C>G	p.Arg24Gly	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.70C>G	p.Arg24Gly	missense_variant	Exon 1 of 3	1	NM_012476.3	ENSP00000234392.2
VAX2	ENST00000432367.6	n.-108C>G		upstream_gene_variant		5		ENSP00000405114.2
ENSG00000296671	ENST00000741094.1	n.-222G>C		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00979 AC: 1489 AN: 152046 Hom.: 32 Cov.: 34

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00136 AC: 16 AN: 11756 AF XY: 0.000849

Gnomad AFR exome AF: 0.0586

Gnomad AMR exome AF: 0.000618

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000811 AC: 953 AN: 1174692 Hom.: 9 Cov.: 33 AF XY: 0.000663 AC XY: 376 AN XY: 567034

African (AFR) AF: 0.0336 AC: 800 AN: 23776

American (AMR) AF: 0.00245 AC: 26 AN: 10624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16448

East Asian (EAS) AF: 0.00 AC: 0 AN: 27032

South Asian (SAS) AF: 0.0000220 AC: 1 AN: 45478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30884

Middle Eastern (MID) AF: 0.000613 AC: 2 AN: 3260

European-Non Finnish (NFE) AF: 0.0000258 AC: 25 AN: 969564

Other (OTH) AF: 0.00208 AC: 99 AN: 47626

GnomAD4 genome AF: 0.00982 AC: 1494 AN: 152166 Hom.: 32 Cov.: 34 AF XY: 0.00975 AC XY: 725 AN XY: 74394

African (AFR) AF: 0.0340 AC: 1414 AN: 41530

American (AMR) AF: 0.00346 AC: 53 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67974

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.0117

ExAC AF: 0.000433 AC: 18

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.17
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.15
Sift	Benign	0.087	T
Sift4G	Benign	0.45	T
Polyphen		0.017	B
Vest4		0.16
MVP		0.85
MPC		0.049
ClinPred		0.057	T
GERP RS		1.8
PromoterAI		0.046	Neutral
Varity_R		0.087
gMVP		0.25
Mutation Taster		=95/5	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

dbSNP: rs2234496; hg19: chr2-71127821;