2-70900691-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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, single submitter B:1
• Conservation: PhyloP100: -0.167

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 Benign. Variant got -14 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_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAX2	NM_012476.3	c.70C>G	p.Arg24Gly	missense_variant	1/3	ENST00000234392.3
VAX2	XM_011532750.4	c.70C>G	p.Arg24Gly	missense_variant	1/4
VAX2	XM_011532751.4	c.70C>G	p.Arg24Gly	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAX2	ENST00000234392.3	c.70C>G	p.Arg24Gly	missense_variant	1/3	1	NM_012476.3	P1

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

GnomAD3 exomes AF: 0.00136 AC: 16 AN: 11756 Hom.: 0 AF XY: 0.000849 AC XY: 6 AN XY: 7068

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 SAS exome AF: 0.000511

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

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.00245

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000258

Gnomad4 OTH exome AF: 0.00208

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

Gnomad4 AFR AF: 0.0340

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00757

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

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
MutationTaster	Benign	1.0	N
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
Varity_R		0.087
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs2234496; hg19: chr2-71127821;