SIK1

salt inducible kinase 1, the group of SIK family kinases

Basic information

Region (hg38): 21:43414482-43427131

Previous symbols: [ "SNF1LK" ]

Links

ENSG00000142178 ∙ NCBI:150094 ∙ OMIM:605705 ∙ HGNC:11142 ∙ Uniprot:P57059 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy (Supportive), mode of inheritance: AD
• early myoclonic encephalopathy (Supportive), mode of inheritance: AD
• West syndrome (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 30 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 30	AD	General	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	Neurologic	25839329
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SIK1 gene.

• Developmental and epileptic encephalopathy, 30 (804 variants)
• Inborn genetic diseases (147 variants)
• not provided (97 variants)
• not specified (2 variants)
• Seizure (2 variants)
• Epileptic encephalopathy (1 variants)
• Language disorder;Global developmental delay (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SIK1 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	218	13	233
missense			329	48	17	394
nonsense		2	5			7
start loss			1			1
frameshift		1	11	2		14
inframe indel			5	1		6
splice donor/acceptor (+/-2bp)			2			2
splice region			15	33	4	52
non coding			2	82	16	100
Total	0	3	357	351	46

Variants in SIK1

This is a list of pathogenic ClinVar variants found in the SIK1 region.

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

Position	Type	Phenotype	Significance	ClinVar
21-43416754-G-A		Developmental and epileptic encephalopathy, 30	Likely benign (Mar 15, 2022)
21-43416760-C-T		Developmental and epileptic encephalopathy, 30	Likely benign (Nov 24, 2020)
21-43416761-G-A		Inborn genetic diseases	Uncertain significance (Jun 21, 2023)
21-43416773-C-G		Developmental and epileptic encephalopathy, 30	Uncertain significance (Feb 09, 2022)
21-43416774-A-C		Developmental and epileptic encephalopathy, 30	Likely benign (Jan 17, 2024)
21-43416774-A-G		Developmental and epileptic encephalopathy, 30	Uncertain significance (Jun 02, 2022)
21-43416783-G-A		Developmental and epileptic encephalopathy, 30	Likely benign (Sep 27, 2022)
21-43416789-C-T		Developmental and epileptic encephalopathy, 30	Likely benign (Nov 21, 2023)
21-43416792-T-C		Developmental and epileptic encephalopathy, 30	Uncertain significance (Jun 14, 2022)
21-43416801-C-A		Developmental and epileptic encephalopathy, 30	Uncertain significance (Jan 04, 2024)
21-43416815-C-T		Developmental and epileptic encephalopathy, 30	Uncertain significance (May 08, 2022)
21-43416822-G-A		Developmental and epileptic encephalopathy, 30	Uncertain significance (Nov 18, 2019)
21-43416831-C-G		Developmental and epileptic encephalopathy, 30	Uncertain significance (Nov 08, 2022)
21-43416836-G-A		Developmental and epileptic encephalopathy, 30	Uncertain significance (Aug 23, 2022)
21-43416836-G-C		Developmental and epileptic encephalopathy, 30	Uncertain significance (Jul 13, 2023)
21-43416837-C-A		Inborn genetic diseases	Likely benign (Jan 04, 2024)
21-43416837-CC-AT		Developmental and epileptic encephalopathy, 30	Uncertain significance (Sep 10, 2023)
21-43416839-A-G		Developmental and epileptic encephalopathy, 30	Uncertain significance (Jun 27, 2023)
21-43416844-G-A		Developmental and epileptic encephalopathy, 30	Likely benign (Mar 13, 2022)
21-43416851-C-A		Developmental and epileptic encephalopathy, 30	Uncertain significance (Oct 16, 2023)
21-43416851-C-T		Developmental and epileptic encephalopathy, 30 • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 25, 2024)
21-43416852-G-A		Developmental and epileptic encephalopathy, 30 • Inborn genetic diseases	Uncertain significance (Jan 17, 2024)
21-43416856-T-C		Developmental and epileptic encephalopathy, 30	Likely benign (Dec 08, 2022)
21-43416864-C-G		Developmental and epileptic encephalopathy, 30	Uncertain significance (Aug 24, 2022)
21-43416864-C-T		Developmental and epileptic encephalopathy, 30	Uncertain significance (Dec 05, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SIK1	protein_coding	protein_coding	ENST00000270162	13	12614

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.937	0.0628	125712	0	26	125738	0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.49	365	454	0.803	0.0000293	4926
Missense in Polyphen		109	199.83	0.54547		2197
Synonymous	0.0809	217	219	0.993	0.0000157	1683
Loss of Function	4.31	5	30.8	0.162	0.00000148	355

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000222	0.000218
Ashkenazi Jewish	0.000109	0.0000992
East Asian	0.0000573	0.0000544
Finnish	0.000204	0.000185
European (Non-Finnish)	0.0000950	0.0000879
Middle Eastern	0.0000573	0.0000544
South Asian	0.0000984	0.0000980
Other	0.000186	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. Phosphorylates HDAC4, HDAC5, PPME1, SREBF1, CRTC1/TORC1 and CRTC2/TORC2. Acts as a tumor suppressor and plays a key role in p53/TP53-dependent anoikis, a type of apoptosis triggered by cell detachment: required for phosphorylation of p53/TP53 in response to loss of adhesion and is able to suppress metastasis. Part of a sodium-sensing signaling network, probably by mediating phosphorylation of PPME1: following increases in intracellular sodium, SIK1 is activated by CaMK1 and phosphorylates PPME1 subunit of protein phosphatase 2A (PP2A), leading to dephosphorylation of sodium/potassium-transporting ATPase ATP1A1 and subsequent increase activity of ATP1A1. Acts as a regulator of muscle cells by phosphorylating and inhibiting class II histone deacetylases HDAC4 and HDAC5, leading to promote expression of MEF2 target genes in myocytes. Also required during cardiomyogenesis by regulating the exit of cardiomyoblasts from the cell cycle via down-regulation of CDKN1C/p57Kip2. Acts as a regulator of hepatic gluconeogenesis by phosphorylating and repressing the CREB-specific coactivators CRTC1/TORC1 and CRTC2/TORC2, leading to inhibit CREB activity. Also regulates hepatic lipogenesis by phosphorylating and inhibiting SREBF1. In concert with CRTC1/TORC1, regulates the light-induced entrainment of the circadian clock by attenuating PER1 induction; represses CREB-mediated transcription of PER1 by phosphorylating and deactivating CRTC1/TORC1 (By similarity). {ECO:0000250|UniProtKB:Q60670, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:16306228, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:19622832}.
• Disease: DISEASE: Epileptic encephalopathy, early infantile, 30 (EIEE30) [MIM:616341]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:25839329}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in SIK1 may be associated with some cancers, such as breast cancers. Loss of SIK1 correlates with poor patient outcome in breast cancers (PubMed:19622832). {ECO:0000269|PubMed:19622832}.
• Pathway: Glucagon signaling pathway - Homo sapiens (human);TGF-beta Signaling Pathway;TGF_beta_Receptor;LKB1 signaling events (Consensus)

Recessive Scores

• pRec: 0.208

Intolerance Scores

• loftool: 0.325
• rvis_EVS: -0.26
• rvis_percentile_EVS: 34.93

Haploinsufficiency Scores

• pHI: 0.210
• hipred: Y
• hipred_score: 0.704
• ghis: 0.517

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.956

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sik1
• Phenotype: skeleton 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); cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region phenotype

Gene ontology

• Biological process: regulation of sodium ion transport;protein phosphorylation;cell cycle;regulation of mitotic cell cycle;regulation of myotube differentiation;negative regulation of triglyceride biosynthetic process;negative regulation of TOR signaling;negative regulation of CREB transcription factor activity;intracellular signal transduction;cellular response to glucose starvation;entrainment of circadian clock by photoperiod;regulation of cell differentiation;negative regulation of gluconeogenesis;protein autophosphorylation;rhythmic process;cardiac muscle cell differentiation;positive regulation of anoikis
• Cellular component: nucleus;cytoplasm;nucleotide-activated protein kinase complex
• Molecular function: magnesium ion binding;protein serine/threonine kinase activity;protein binding;ATP binding;cAMP response element binding protein binding;protein kinase binding;14-3-3 protein binding