SIK1

protein-coding

salt inducible kinase 1, the group of SIK family kinases

Gene summary

This gene encodes a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. The encoded protein is a member of the adenosine monophosphate-activated kinase (AMPK) subfamily of kinases that play a role in conserved signal transduction pathways. A mutation in this gene is associated with early infantile epileptic encephalopathy 30. [provided by RefSeq, Nov 2016]

Previous symbols:

SNF1LK

MANE transcript

NM_173354.5

Inheritance

ClinVar variants

P:10U:467B:408

Top phenotype

Developmental and epileptic encephalopathy 30

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr21:43,414,483-43,427,131

External References & Databases

Ensembl (ENSG00000142178)

Transcript & Mutation Effects

hg38 • Region Span ~12.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

genetic developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Orphanet

developmental and epileptic encephalopathy, 30DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014595

Submitter: G2P

generalized epilepsyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100574

Submitter: Ambry Genetics

genetic developmental and epileptic encephalopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

*SIK1* was first reported in relation to autosomal dominant developmental and epileptic encephalopathy (AD-DEE) in 2015 (Hansen et al., PMID: 25839329). SIK1 is a member of the AMP kinase (AMPK) subfamily and encodes salt-induced kinase 1, a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. The gene plays a role in the central nervous system, neuronal development, and a signal transduction pathway involved in nuclear regulation of gene expression (PMID: 25839329). Four missense variants and three nonsense variants reported in seven probands across two publications (PMIDs: 25839329, 35267137) have been included in this curation. All nonsense variants were downgraded because of functional evidence from Hansen et al. (PMID:25839329) suggesting that p.Glu347Ter, p.Gln614Ter, and p.Gln663Ter all generate a truncated form of SIK1 that is resistant to degradation. The mechanism of pathogenicity is unclear. In summary, there is limited evidence to support the relationship between SIK1 and autosomal dominant developmental and epileptic encephalopathy (AD-DEE). Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. The gene-disease pair was originally evaluated by the Epilepsy GCEP on 10/2/2018 and reached a classification of limited. In 2021, this record went through administrative changes to update the disease term. Evidence was reevaluated on 5/7/2024 under SOP v.10.1. As a result of this reevaluation, the classification did not change and remains at limited.

developmental and epileptic encephalopathy, 30STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014595

Submitter: Labcorp Genetics (formerly Invitae)

genetic developmental and epileptic encephalopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 30AD

Manifestation: Neurologic

Intervention: General

Rationale: 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

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 25839329

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIK1 variants in ClinVar

8 Conditions Cataloged

Developmental and epileptic encephalopathy, 30Total: 1020

Inborn genetic diseasesTotal: 218

not providedTotal: 151

not specifiedTotal: 53

Epileptic encephalopathyTotal: 1

Language disorderTotal: 1

Global developmental delayTotal: 1

SeizureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173354.5. 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	283 clinvar	10 clinvar	297
missense	2 clinvar		436 clinvar	102 clinvar	11 clinvar	551
nonsense	2 clinvar	3 clinvar	6 clinvar			11
start loss			1 clinvar			1
frameshift		3 clinvar	16 clinvar	2 clinvar		21
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	4	6	467	387	21	885

Highest pathogenic variant AF is 0.0000029421803

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173354.5	RefSeq	NP_775490.2	13	MANE Select
ENST00000270162.8	Ensembl	ENSP00000270162.6	13	MANE Select
ENST00000644750.1	Ensembl	ENSP00000495479.1	4	Standard
ENST00000880889.1	Ensembl	ENSP00000550948.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glucagon signaling pathway - Homo sapiens (human)
TGF-beta Signaling Pathway
TGF_beta_Receptor
LKB1 signaling events

Biological Process

regulation of sodium ion transport
protein phosphorylation
cell cycle
regulation of mitotic cell cycle
regulation of myotube differentiation

Molecular Function

magnesium ion binding
protein serine/threonine kinase activity
protein binding
ATP binding
cAMP response element binding protein binding

Cellular Component

nucleus
cytoplasm
nucleotide-activated protein kinase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000270162
Coding exons: 13
Length: 12614
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125738
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.49	365	454	0.803	0.0000293	4926
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000066	0.000062	rare
Latino/Admixed American	0.00016	0.00014	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.000057	0.000054	rare
Finnish	0.00020	0.00018	rare
European (Non-Finnish)	0.000095	0.000088	rare
South Asian	0.000098	0.000098	rare
Other	0.00019	0.00016	rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.208

Intolerance Scores

LoFtool: 0.325
RVIS EVS: -0.26
RVIS percentile EVS: 34.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.956

Gene Damage Prediction

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