2-70900752-C-A

Variant names:

• chr2-70900752-C-A
• rs966757865
• NM_012476.3:c.131C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012476.3(VAX2):​c.131C>A​(p.Thr44Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000752 in 1,329,612 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: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: VAX2 NM_012476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.281
• 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]

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=0.056784302).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012476.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAX2	NM_012476.3	MANE Select	c.131C>A	p.Thr44Lys	missense	Exon 1 of 3	NP_036608.1	F1T0K5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAX2	ENST00000234392.3	TSL:1 MANE Select	c.131C>A	p.Thr44Lys	missense	Exon 1 of 3	ENSP00000234392.2	Q9UIW0
	VAX2	ENST00000432367.6	TSL:5	n.-47C>A		upstream_gene	N/A	ENSP00000405114.2	C9J5E3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.52e-7 AC: 1 AN: 1329612 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 655042

African (AFR) AF: 0.00 AC: 0 AN: 27550

American (AMR) AF: 0.0000339 AC: 1 AN: 29534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23540

East Asian (EAS) AF: 0.00 AC: 0 AN: 29640

South Asian (SAS) AF: 0.00 AC: 0 AN: 72622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3928

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047278

Other (OTH) AF: 0.00 AC: 0 AN: 54820

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.2
DANN	Benign	0.81
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.28
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.57	N
REVEL	Benign	0.14
Sift	Benign	0.92	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.080
MutPred		0.28		Gain of ubiquitination at T44 (P = 0.0022)
MVP		0.68
MPC		0.046
ClinPred		0.069	T
GERP RS		-4.0
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.24
Mutation Taster		=97/3	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: rs966757865; hg19: chr2-71127882;