ARNT2

protein-coding

aryl hydrocarbon receptor nuclear translocator 2, the group of Basic helix-loop-helix proteins|PAS domain containing|MicroRNA protein coding host genes

Gene summary

This gene encodes a member of the basic-helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily of transcription factors. The encoded protein acts as a partner for several sensor proteins of the bHLH-PAS family, forming heterodimers with the sensor proteins that bind regulatory DNA sequences in genes responsive to developmental and environmental stimuli. Under hypoxic conditions, the encoded protein complexes with hypoxia-inducible factor 1alpha in the nucleus and this complex binds to hypoxia-responsive elements in enhancers and promoters of oxygen-responsive genes. A highly similar protein in mouse forms functional complexes with both aryl hydrocarbon receptors and Single-minded proteins, suggesting additional roles for the encoded protein in the metabolism of xenobiotic compounds and the regulation of neurogenesis, respectively. [provided by RefSeq, Dec 2013]

MANE transcript

NM_014862.4

Inheritance

AD, AR

ClinVar variants

P:9U:134B:68

Top phenotype

Webb-Datani syndrome

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr15:80,404,350-80,597,933

External References & Databases

Ensembl (ENSG00000172379)

Transcript & Mutation Effects

hg38 • Region Span ~193.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

septooptic dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008428

Submitter: Orphanet

Webb-Dattani syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014404

Submitter: G2P

Webb-Dattani syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014404

Submitter: PanelApp Australia

Webb-Dattani syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014404

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Webb-Datani syndromeAR

Manifestation: Craniofacial; Endocrine; Neurologic; Ophthalmologic; Renal

Intervention: Endocrine; Renal

Rationale: The condition may involve multiple pituitary hormone deficiencies, and awareness may allow early recognition and treatment; Awareness of the risk of renal manifestations such as hydronephrosis and vesicoureteral reflux may allow surveillance and renal-protective measures

Refs: 24022475

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARNT2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 177

not specifiedTotal: 88

ARNT2-related disorderTotal: 13

Webb-Dattani syndromeTotal: 12

Gnb5-related intellectual disability-cardiac arrhythmia syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014862.4. 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			4 clinvar	61 clinvar	3 clinvar	68
missense			126 clinvar	4 clinvar		130
nonsense	3 clinvar	2 clinvar	1 clinvar			6
start loss						0
frameshift	3 clinvar		1 clinvar			4
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	6	3	134	65	3	211

Highest pathogenic variant AF is 0.0000061564815

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014862.4	RefSeq	NP_055677.3	19	MANE Select
ENST00000303329.9	Ensembl	ENSP00000307479.4	19	MANE Select
ENST00000525103.1	Ensembl	ENSP00000452961.1	5	Standard
ENST00000527771.5	Ensembl	ENSP00000453792.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
arnt2	Danio rerio	Structure: dopaminergic neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

arnt2

Danio rerio

Structure: dopaminergic neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Renal cell carcinoma - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Transcriptional misregulation in cancer - Homo sapiens (human)
Type 2 papillary renal cell carcinoma
Aryl hydrocarbon receptor signalling

Biological Process

response to hypoxia
in utero embryonic development
regulation of transcription, DNA-templated
xenobiotic metabolic process
central nervous system development

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
DNA-binding transcription factor activity
protein binding

Cellular Component

nucleus
nucleoplasm
transcription factor complex
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000303329
Coding exons: 19
Length: 193587
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125747
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.98	322	439	0.734	0.0000264	4723
Missense (PolyPhen)		25	40.916	0.61101		364
Synonymous	0.312	166	171	0.970	0.0000112	1378
Loss of Function	5.04	6	40.7	0.147	0.00000190	464

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0	0.0	absent
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that plays a role in the development of the hypothalamo-pituitary axis, postnatal brain growth, and visual and renal function (PubMed:24022475). Specifically recognizes the xenobiotic response element (XRE). {ECO:0000269|PubMed:24022475}.;
Disease: DISEASE: Webb-Dattani syndrome (WEDAS) [MIM:615926]: A disorder characterized by postnatal microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, global developmental delay, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract. {ECO:0000269|PubMed:24022475}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.186

Intolerance Scores

LoFtool: 0.274
RVIS EVS: -0.84
RVIS percentile EVS: 11.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.983

Gene Damage Prediction

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