NPAS2

neuronal PAS domain protein 2, the group of Basic helix-loop-helix proteins|PAS domain containing

Basic information

Region (hg38): 2:100820138-100996829

Links

ENSG00000170485 ∙ NCBI:4862 ∙ OMIM:603347 ∙ HGNC:7895 ∙ Uniprot:Q99743 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPAS2 gene.

• Inborn genetic diseases (25 variants)
• not provided (21 variants)
• Non-obstructive azoospermia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPAS2 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				6	4	10
missense		1	27	2	3	33
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				1	1	2
non coding				1	1	2
Total	0	1	27	9	8

Variants in NPAS2

This is a list of pathogenic ClinVar variants found in the NPAS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-100925265-A-G		not specified	Uncertain significance (Jun 29, 2023)
2-100925274-G-C		NPAS2-related disorder	Benign (Mar 16, 2020)
2-100925290-C-G		not specified	Uncertain significance (Oct 27, 2022)
2-100925292-A-G		not specified	Uncertain significance (Jan 04, 2022)
2-100932919-C-T		not specified	Uncertain significance (Jul 26, 2022)
2-100932943-A-G		not specified	Uncertain significance (Sep 14, 2022)
2-100937826-T-C		not specified	Uncertain significance (Aug 08, 2023)
2-100948320-T-C		not specified	Uncertain significance (Aug 08, 2022)
2-100949375-G-A		not specified	Uncertain significance (May 04, 2022)
2-100949469-C-G		not specified	Uncertain significance (Feb 01, 2023)
2-100964065-C-G		not specified	Uncertain significance (Sep 26, 2023)
2-100964082-T-G		not specified	Uncertain significance (May 31, 2023)
2-100964091-C-T			Uncertain significance (Jan 01, 2022)
2-100964875-T-G			Likely benign (Jul 21, 2018)
2-100965766-C-T			Likely benign (Dec 01, 2022)
2-100968275-C-T			Benign (Dec 31, 2019)
2-100971036-G-A		not specified	Uncertain significance (Feb 21, 2024)
2-100974804-A-G		not specified	Uncertain significance (Apr 08, 2022)
2-100974814-A-G			Benign (Dec 31, 2019)
2-100974862-G-C			Likely benign (Jan 25, 2018)
2-100974875-A-G		not specified	Uncertain significance (Dec 27, 2022)
2-100974878-C-G			Benign (Dec 31, 2019)
2-100974889-G-A			Benign (Dec 31, 2019)
2-100974910-C-T			Benign (Dec 31, 2019)
2-100974929-A-G		not specified	Uncertain significance (Dec 30, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPAS2	protein_coding	protein_coding	ENST00000335681	20	176678

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000106	125733	0	4	125737	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.50	333	489	0.681	0.0000290	5354
Missense in Polyphen		75	169.17	0.44334		1997
Synonymous	0.478	198	207	0.958	0.0000138	1619
Loss of Function	6.09	2	47.2	0.0424	0.00000218	521

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000581	0.0000581
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000186	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time- keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. The NPAS2-ARNTL/BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. NPAS2 plays an important role in sleep homeostasis and in maintaining circadian behaviors in normal light/dark and feeding conditions and in the effective synchronization of feeding behavior with scheduled food availability. Regulates the gene transcription of key metabolic pathways in the liver and is involved in DNA damage response by regulating several cell cycle and DNA repair genes. {ECO:0000269|PubMed:11441146, ECO:0000269|PubMed:11441147, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:18439826, ECO:0000269|PubMed:18819933}.
• Pathway: Circadian rhythm - Homo sapiens (human);Circadian Clock;Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha);RORA activates gene expression;NR1D1 (REV-ERBA) represses gene expression;Circadian Clock;BMAL1:CLOCK,NPAS2 activates circadian gene expression;Circadian rhythm pathway (Consensus)

Recessive Scores

• pRec: 0.228

Intolerance Scores

• loftool: 0.119
• rvis_EVS: -0.51
• rvis_percentile_EVS: 21.77

Haploinsufficiency Scores

• pHI: 0.219
• hipred: Y
• hipred_score: 0.822
• ghis: 0.425

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.949

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Npas2
• Phenotype: homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); 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)

Gene ontology

• Biological process: cellular response to DNA damage stimulus;central nervous system development;circadian rhythm;regulation of lipid metabolic process;circadian regulation of gene expression;positive regulation of DNA repair;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;response to redox state;negative regulation of cell death;regulation of response to DNA damage stimulus
• Cellular component: nucleus;nucleoplasm;transcription factor complex;cytosol
• Molecular function: RNA polymerase II distal enhancer sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;protein binding;metal ion binding;protein dimerization activity;Hsp90 protein binding