VSX2

protein-coding

visual system homeobox 2, the group of PRD class homeoboxes and pseudogenes

Gene summary

This gene encodes a homeobox protein originally described as a retina-specific transcription factor. Mutations in this gene are associated with microphthalmia, cataracts and iris abnormalities. [provided by RefSeq, Oct 2009]

Previous symbols:

HOX10
CHX10

MANE transcript

NM_182894.3

Inheritance

AR, AD

ClinVar variants

P:52U:105B:204

Top phenotype

Microphthalmia, isolated 2; Microphthalmia/coloboma 3

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr14:74,239,449-74,262,738

External References & Databases

Ensembl (ENSG00000119614)

Transcript & Mutation Effects

hg38 • Region Span ~23.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microphthalmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0021129

Submitter: Ambry Genetics

microphthalmia, isolated, with coloboma 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012408

Submitter: G2P

isolated microphthalmia 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012409

Submitter: G2P

microphthalmia, isolated, with coloboma 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012408

Submitter: PanelApp Australia

microphthalmia, isolated, with colobomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000170

Submitter: Orphanet

microphthalmia, isolated, with coloboma 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012408

Submitter: Natera

microphthalmia, isolated, with coloboma 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012408

Submitter: Labcorp Genetics (formerly Invitae)

isolated microphthalmia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012409

Submitter: PanelApp Australia

isolated anophthalmia-microphthalmia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016764

Submitter: Orphanet

Clinical Genomic Database (CGD)

Microphthalmia, isolated 2; Microphthalmia/coloboma 3AR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 3378363; 10932181; 15257456; 17661825; 18648522

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VSX2 variants in ClinVar

12 Conditions Cataloged

Isolated microphthalmia 2Total: 326

MicrophthalmiaTotal: 72

Inborn genetic diseasesTotal: 57

not providedTotal: 45

Microphthalmia, isolated, with coloboma 3Total: 42

VSX2-related disorderTotal: 12

not specifiedTotal: 3

Microphthalmia, cataracts, and iris abnormalitiesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182894.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	198 clinvar		204
missense	2 clinvar	6 clinvar	99 clinvar	5 clinvar	1 clinvar	113
nonsense	6 clinvar	4 clinvar				10
start loss		1 clinvar				1
frameshift	16 clinvar	11 clinvar				27
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar				6
Total	26	26	105	203	1	361

Highest pathogenic variant AF is 0.000022923246

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182894.3	RefSeq	NP_878314.1	5	MANE Select
ENST00000261980.3	Ensembl	ENSP00000261980.2	5	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
vsx2	Danio rerio	Structure: retinal bipolar neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

vsx2

Danio rerio

Structure: retinal bipolar neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
multicellular organism development
visual perception
response to stimulus

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
sequence-specific DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261980
Coding exons: 5
Length: 23267
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125742
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.561	201	225	0.895	0.0000131	2288
Missense (PolyPhen)		63	75.633	0.83297		776
Synonymous	-1.13	116	102	1.14	0.00000644	722
Loss of Function	1.46	8	13.8	0.578	6.60e-7	152

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000058	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000063	0.000062	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a significant role in the specification and morphogenesis of the sensory retina. May also participate in the development of the cells of the inner nuclear layer, particularly bipolar cells (By similarity). {ECO:0000250}.;
Disease: DISEASE: Microphthalmia with cataracts and iris abnormalities (MCOPCTI) [MIM:610092]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, cataract and other abnormalities like cataract may also be present. {ECO:0000269|PubMed:10932181}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Microphthalmia, isolated, with coloboma, 3 (MCOPCB3) [MIM:610092]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269|PubMed:15257456, ECO:0000269|PubMed:24033328}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.240

Intolerance Scores

LoFtool: 0.164
RVIS EVS: -0.29
RVIS percentile EVS: 32.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.870

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium