RAX2

protein-coding

retina and anterior neural fold homeobox 2, the group of PRD class homeoboxes and pseudogenes

Gene summary

This gene encodes a homeodomain-containing protein that plays a role in eye development. Mutation of this gene causes age-related macular degeneration type 6, an eye disorder resulting in accumulations of protein and lipid beneath the retinal pigment epithelium and within the Bruch's membrane. Defects in this gene can also cause cone-rod dystrophy type 11, a disease characterized by the initial degeneration of cone photoreceptor cells and resulting in loss of color vision and visual acuity, followed by the degeneration of rod photoreceptor cells, which progresses to night blindness and the loss of peripheral vision. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

Previous symbols:

RAXL1

MANE transcript

NM_001319074.4

Inheritance

AD, AR

ClinVar variants

P:17U:138B:77

Top phenotype

Cone-rod dystrophy 11; Retinitis pigmentosa 95

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr19:3,769,089-3,772,228

External References & Databases

Ensembl (ENSG00000173976)

Transcript & Mutation Effects

hg38 • Region Span ~3.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cone-rod dystrophy 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012483

Submitter: PanelApp Australia

retinitis pigmentosa 95STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859308

Submitter: PanelApp Australia

retinitis pigmentosaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: G2P

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

cone-rod dystrophy 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012483

Submitter: Labcorp Genetics (formerly Invitae)

cone-rod dystrophy 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012483

Submitter: G2P

retinitis pigmentosa 95STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859308

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 95LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859308

Submitter: Ambry Genetics

retinitis pigmentosaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: Franklin by Genoox

Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) https://www.nature.com/articles/s41436-018-0345-5

Clinical Genomic Database (CGD)

Cone-rod dystrophy 11; Retinitis pigmentosa 95AD/AR

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: 15028672; 30377383

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAX2 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 228

not specifiedTotal: 82

RAX2-related disorderTotal: 46

Cone-rod dystrophy 11Total: 29

Age related macular degeneration 6Total: 24

Retinitis pigmentosa 95Total: 9

Retinal dystrophyTotal: 7

Macular degenerationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001319074.4. 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			1 clinvar	64 clinvar	1 clinvar	66
missense	2 clinvar	5 clinvar	129 clinvar	11 clinvar	1 clinvar	148
nonsense		1 clinvar	2 clinvar			3
start loss	2 clinvar					2
frameshift	3 clinvar	1 clinvar	6 clinvar			10
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar				3
Total	9	8	138	75	2	232

Highest pathogenic variant AF is 0.000045451055

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001319074.4	RefSeq	NP_001306003.2	2	MANE Select
ENST00000555633.3	Ensembl	ENSP00000450456.3	2	MANE Select
NM_032753.4	RefSeq	NP_116142.1	2	Standard
ENST00000555978.5	Ensembl	ENSP00000450687.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

visual perception
positive regulation of transcription by RNA polymerase II
response to stimulus

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000555633
Coding exons: 2
Length: 3147
Individuals with no LoFs: 108910
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 108913
p: 0.0000138

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.169	118	123	0.957	0.00000905	1126
Missense (PolyPhen)		53	56.919	0.93115		528
Synonymous	0.877	50	58.5	0.854	0.00000436	421
Loss of Function	0.208	3	3.41	0.879	1.47e-7	38

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000067	0.000066	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000011	0.000010	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in modulating the expression of photoreceptor specific genes. Binds to the Ret-1 and Bat-1 element within the rhodopsin promoter. {ECO:0000269|PubMed:15028672}.;
Disease: DISEASE: Macular degeneration, age-related, 6 (ARMD6) [MIM:613757]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:15028672}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Cone-rod dystrophy 11 (CORD11) [MIM:610381]: An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. {ECO:0000269|PubMed:15028672}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.175

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.228

Gene Damage Prediction

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