PHOX2B

paired like homeobox 2B, the group of PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): 4:41744081-41748725

Previous symbols: [ "PMX2B" ]

Links

ENSG00000109132 ∙ NCBI:8929 ∙ OMIM:603851 ∙ HGNC:9143 ∙ Uniprot:Q99453 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (Definitive), mode of inheritance: AD
• congenital central hypoventilation syndrome (Supportive), mode of inheritance: AD
• Haddad syndrome (Supportive), mode of inheritance: AD
• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (Definitive), mode of inheritance: AD
• neuroblastoma, susceptibility to, 2 (Strong), mode of inheritance: AD
• neuroblastoma, susceptibility to, 2 (Definitive), mode of inheritance: AD
• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (Strong), mode of inheritance: AD
• Haddad syndrome (Definitive), mode of inheritance: AD
• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Central hypoventilation syndrome, congenital 1; Neuroblastoma with Hirschsprung disease; Neuroblastoma, susceptiblity to, 2	AD	Neurologic; Oncologic	In Central hypoventilation syndrome, congenital, early recognition and interventions to support ventilation (as well as avoidance of exacerbating factors) can reduce morbidity and mortality; In Neuroblastoma, susceptibility to, 2 and Neuroblastoma with Hirschsprung disease, surveillance and/or awareness of cancer risk (involving the sympathetic nervous system) may allow early diagnosis and treatment of tumors, which may reduce morbidity and mortality	Gastrointestinal; Neurologic; Oncologic	10390427; 12640453; 14566559; 15024693; 16873766; 16691592; 20301600; 32073407
Individuals are also at risk of additional autonomic nervous system anomalies including Hirschsprung disease

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PHOX2B gene.

• Haddad syndrome (644 variants)
• Hereditary cancer-predisposing syndrome (580 variants)
• Neuroblastoma, susceptibility to, 2 (89 variants)
• not provided (77 variants)
• Congenital central hypoventilation (77 variants)
• not specified (18 variants)
• PHOX2B-related condition (11 variants)
• Neuroblastoma, susceptibility to, 2;Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (9 variants)
• Neuroblastoma (4 variants)
• Inborn genetic diseases (3 variants)
• Ovarian cancer (3 variants)
• Congenital central hypoventilation;Neuroblastoma, susceptibility to, 2 (2 variants)
• Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (2 variants)
• Predisposition to neuroblastoma (1 variants)
• Congenital central hypoventilation syndrome, with or without Hirschsprung disease (1 variants)
• Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease;Neuroblastoma, susceptibility to, 2 (1 variants)
• Hirschsprung disease-ganglioneuroblastoma syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PHOX2B gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	299	3	304
missense	2	1	424		3	430
nonsense	8	2	4			14
start loss			2			2
frameshift	19	5	1			25
inframe indel	20	3	25	14		62
splice donor/acceptor (+/-2bp)	1	3	2			6
splice region			11	14		25
non coding			21	35	17	73
Total	50	14	481	348	23

Highest pathogenic variant AF is 0.0000138

Variants in PHOX2B

This is a list of pathogenic ClinVar variants found in the PHOX2B region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-41744106-T-C		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Uncertain significance (Jan 13, 2018)
4-41744145-T-A		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Benign (Jan 12, 2018)
4-41744163-T-A		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Uncertain significance (Jan 12, 2018)
4-41744180-C-T		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Uncertain significance (Jan 12, 2018)
4-41744225-A-G		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Uncertain significance (Mar 16, 2018)
4-41744321-A-G		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Uncertain significance (Jan 13, 2018)
4-41744406-G-C		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Uncertain significance (Jan 12, 2018)
4-41744420-G-A		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Benign (Jan 13, 2018)
4-41744426-G-A		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Benign (Jan 13, 2018)
4-41744443-C-T		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Benign (Jan 13, 2018)
4-41744460-T-C		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Benign (Jan 13, 2018)
4-41744462-C-A		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Uncertain significance (Jan 12, 2018)
4-41744473-C-G		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Uncertain significance (Jan 12, 2018)
4-41744497-C-A		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Uncertain significance (Jan 13, 2018)
4-41744538-T-C		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Uncertain significance (Jan 13, 2018)
4-41744651-G-T		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Benign (Jan 13, 2018)
4-41744681-G-C		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Benign (Jan 13, 2018)
4-41744969-T-C		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Benign (Jan 13, 2018)
4-41745018-C-T		Neuroblastoma, susceptibility to, 2 • Congenital central hypoventilation	Uncertain significance (Jan 12, 2018)
4-41745070-G-A		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Uncertain significance (Jan 13, 2018)
4-41745114-G-A		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Uncertain significance (Jan 13, 2018)
4-41745127-G-C		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Uncertain significance (Jan 12, 2018)
4-41745132-T-TA		Neuroblastoma • Congenital central hypoventilation	Benign (Jun 14, 2016)
4-41745169-C-G		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Uncertain significance (Jan 13, 2018)
4-41745207-A-C		Congenital central hypoventilation • Neuroblastoma, susceptibility to, 2	Benign (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PHOX2B	protein_coding	protein_coding	ENST00000226382	3	4889

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.938	0.0622	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.08	93	169	0.549	0.00000760	1988
Missense in Polyphen		12	44.162	0.27173		536
Synonymous	-1.11	85	72.9	1.17	0.00000346	666
Loss of Function	2.75	0	8.80	0.00	3.76e-7	102

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus. Transcription factor which could determine a neurotransmitter phenotype in vertebrates. Enhances second-messenger-mediated activation of the dopamine beta-hydrolase and c-fos promoters, and of several enhancers including cAMP-response element and serum- response element.
• Disease: DISEASE: Neuroblastoma 2 (NBLST2) [MIM:613013]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. {ECO:0000305|PubMed:15024693}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Neural Crest Differentiation;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways (Consensus)

Recessive Scores

• pRec: 0.281

Intolerance Scores

• loftool: 0.0467
• rvis_EVS: 0.13
• rvis_percentile_EVS: 62.74

Haploinsufficiency Scores

• pHI: 0.629
• hipred: Y
• hipred_score: 0.789

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.626

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Phox2b
• Phenotype: vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; embryo phenotype; cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: phox2bb
• Affected structure: enteric nervous system
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: neuron migration;regulation of respiratory gaseous exchange by neurological system process;noradrenergic neuron differentiation;noradrenergic neuron development;brainstem development;nervous system development;negative regulation of cell population proliferation;glial cell differentiation;regulation of gene expression;positive regulation of G2/M transition of mitotic cell cycle;cell differentiation in hindbrain;medullary reticular formation development;hindbrain tangential cell migration;skeletal muscle cell differentiation;negative regulation of neuron differentiation;positive regulation of neuron differentiation;positive regulation of transcription by RNA polymerase II;autonomic nervous system development;enteric nervous system development;sympathetic nervous system development;parasympathetic nervous system development;inner ear development;efferent axon development in a lateral line nerve;respiratory system development;retrotrapezoid nucleus neuron differentiation;sympathetic ganglion development;negative regulation of cell cycle arrest;dopaminergic neuron differentiation;cellular response to BMP stimulus;positive regulation of cold-induced thermogenesis;neural crest cell migration involved in autonomic nervous system development
• Cellular component: nuclear chromatin;nucleus;nucleoplasm
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;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