PER2

period circadian regulator 2, the group of PAS domain containing

Basic information

Region (hg38): 2:238244043-238290102

Links

ENSG00000132326 ∙ NCBI:8864 ∙ OMIM:603426 ∙ HGNC:8846 ∙ Uniprot:O15055 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• advanced sleep phase syndrome (Supportive), mode of inheritance: AD
• advanced sleep phase syndrome 1 (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Advanced sleep phase syndrome, familial,1	AD	General	The clinical relevance of the condition is unclear	Neurologic	15800623

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PER2 gene.

• Inborn genetic diseases (47 variants)
• not provided (27 variants)
• Advanced sleep phase syndrome 1 (7 variants)
• Autism spectrum disorder (2 variants)
• PER2-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PER2 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	10	16
missense			48	12	3	63
nonsense						0
start loss						0
frameshift	1					1
inframe indel						0
splice donor/acceptor (+/-2bp)			2			2
splice region				2		2
non coding						0
Total	1	0	50	18	13

Variants in PER2

This is a list of pathogenic ClinVar variants found in the PER2 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-238246395-T-C		not specified	Uncertain significance (Jan 23, 2023)
2-238246401-T-C		not specified	Uncertain significance (Dec 15, 2023)
2-238246436-G-A		PER2-related disorder	Benign (Oct 28, 2019)
2-238246444-G-A		PER2-related disorder	Likely benign (Jun 11, 2019)
2-238246445-C-T		not specified	Uncertain significance (Oct 22, 2021)
2-238246463-A-G		not specified	Uncertain significance (Oct 05, 2023)
2-238246532-G-A			Likely benign (Sep 28, 2018)
2-238249064-C-G		not specified	Uncertain significance (Nov 08, 2021)
2-238250569-G-A		not specified	Uncertain significance (Nov 30, 2022)
2-238250598-C-A		not specified	Uncertain significance (Dec 20, 2023)
2-238250642-G-A		Advanced sleep phase syndrome 1	Uncertain significance (Mar 26, 2021)
2-238250644-T-C		not specified	Uncertain significance (Dec 06, 2021)
2-238250655-C-T		not specified	Uncertain significance (Apr 26, 2023)
2-238250744-C-T		PER2-related disorder	Uncertain significance (Jul 27, 2023)
2-238251623-A-G			Likely benign (Dec 31, 2019)
2-238253011-A-G		PER2-related disorder	Likely benign (Jul 30, 2019)
2-238253021-T-C		not specified	Uncertain significance (Feb 13, 2024)
2-238253027-G-A		not specified	Uncertain significance (Dec 27, 2023)
2-238253060-G-A		Advanced sleep phase syndrome 1	Uncertain significance (-)
2-238253086-CGGTGGGGAGGCCCTACCCATGGCCGAT-C		PER2-related disorder	Likely benign (Jul 01, 2020)
2-238253103-C-T		not specified	Uncertain significance (May 03, 2023)
2-238253135-G-A		not specified	Uncertain significance (Oct 18, 2021)
2-238253139-A-G		not specified	Uncertain significance (Aug 28, 2023)
2-238253162-G-A		not specified	Uncertain significance (May 31, 2023)
2-238253164-G-A			Likely benign (Jan 03, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PER2	protein_coding	protein_coding	ENST00000254657	22	46065

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.715	0.285	125696	0	52	125748	0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.427	706	739	0.956	0.0000459	8230
Missense in Polyphen		180	232.6	0.77387		2772
Synonymous	-0.503	334	323	1.04	0.0000239	2480
Loss of Function	5.31	11	52.5	0.209	0.00000276	629

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000329	0.000329
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000510	0.000508
European (Non-Finnish)	0.000150	0.000149
Middle Eastern	0.00	0.00
South Asian	0.000327	0.000327
Other	0.000979	0.000978

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional repressor 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 syndrome 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. PER1 and PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate circadian timing, but also contribute directly to repression of clock-controlled target genes through interaction with several classes of RNA-binding proteins, helicases and others transcriptional repressors. PER appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK- ARTNL/BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes, like PER2 itself or PER1. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3' termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK-ARTNL/BMAL1 interactions. Recruitment of large PER complexes to the elongating polymerase at PER and CRY termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. May propagate clock information to metabolic pathways via the interaction with nuclear receptors. Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at the promoter of nuclear receptors target genes like ARNTL or G6PC. Directly and specifically represses PPARG proadipogenic activity by blocking PPARG recruitment to target promoters and thereby inhibiting transcriptional activation. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of cardiovascular functions through the regulation of NO and vasodilatatory prostaglandins production in aortas. Controls circadian glutamate uptake in synaptic vesicles through the regulation of VGLUT1 expression. May also be involved in the regulation of inflammatory processes. Represses the CLOCK- ARNTL/BMAL1 induced transcription of BHLHE40/DEC1 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1. {ECO:0000250|UniProtKB:O54943}.
• Disease: DISEASE: Advanced sleep phase syndrome, familial, 1 (FASPS1) [MIM:604348]: A disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms. {ECO:0000269|PubMed:11232563}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Circadian rhythm - Homo sapiens (human);Acute myeloid leukemia - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Circadian Clock;Melatonin metabolism and effects;BMAL1-CLOCK,NPAS2 activates circadian gene expression;Exercise-induced Circadian Regulation;Circadian Clock;Circadian rhythm pathway (Consensus)

Recessive Scores

• pRec: 0.244

Intolerance Scores

• loftool: 0.475
• rvis_EVS: -1.18
• rvis_percentile_EVS: 5.92

Haploinsufficiency Scores

• pHI: 0.797
• hipred: Y
• hipred_score: 0.722
• ghis: 0.495

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.804

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Per2
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; reproductive system phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands 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); hematopoietic system phenotype; growth/size/body region 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); digestive/alimentary phenotype; renal/urinary system phenotype; skeleton phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); neoplasm; pigmentation phenotype

Zebrafish Information Network

• Gene name: per2
• Affected structure: intersegmental vessel
• Phenotype tag: abnormal
• Phenotype quality: increased length

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;response to ischemia;glycogen biosynthetic process;gluconeogenesis;fatty acid metabolic process;circadian rhythm;response to light stimulus;regulation of vasoconstriction;lactate biosynthetic process;negative regulation of protein ubiquitination;circadian regulation of gene expression;regulation of circadian rhythm;negative regulation of circadian rhythm;entrainment of circadian clock by photoperiod;negative regulation of transcription, DNA-templated;regulation of neurogenesis;regulation of insulin secretion;white fat cell differentiation;regulation of cell cycle;regulation of glutamate uptake involved in transmission of nerve impulse;negative regulation of fat cell proliferation;histone H3 deacetylation;circadian regulation of translation;positive regulation of cold-induced thermogenesis;positive regulation of nucleic acid-templated transcription;negative regulation of transcription regulatory region DNA binding
• Cellular component: nucleus;nucleolus;cytoplasm;perinuclear region of cytoplasm
• Molecular function: transcription regulatory region sequence-specific DNA binding;transcription corepressor binding;transcription coactivator activity;protein binding;transcription factor binding