TLK2

protein-coding

tousled like kinase 2

Gene summary

This gene encodes a nuclear serine/threonine kinase that was first identified in Arabidopsis. The encoded protein is thought to function in the regulation of chromatin assembly in the S phase of the cell cycle by regulating the levels of a histone H3/H4 chaperone. This protein is associated with double-strand break repair of DNA damage caused by radiation. Pseudogenes of this gene are present on chromosomes 10 and 17. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

MANE transcript

NM_006852.6

Inheritance

AD, SD

ClinVar variants

P:106U:162B:34

Top phenotype

Intellectual developmental disorder, autosomal dominant 57

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr17:62,458,658-62,615,481

External References & Databases

Ensembl (ENSG00000146872)

Transcript & Mutation Effects

hg38 • Region Span ~156.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 57STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054837

Submitter: Illumina

intellectual developmental disorder, autosomal dominant 57DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0054837

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 57STRONG

Inheritance Pattern: SD

Disease ID:MONDO:0054837

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*TLK2* encodes a serine-threonine kinase involved in chromatin assembly, and DNA replication, transcription, and repair. Although *de novo* variants in *TLK2* had been observed in large-scale sequencing studies of individuals with neurodevelopmental disorders since 2014 (PMIDs: 25363768, 25533962), the first report highlighting *TLK2* variants as a cause of autosomal dominant complex neurodevelopmental disorder was published in 2016 (Lelieveld et al., PMID: 27479843). The disorder is characterized by a highly variable phenotype, including global developmental delay; borderline, mild or moderate intellectual disability; behavioral disorders including autism; gastrointestinal problems; and facial dysmorphism (PMID: 29861108). Other variable features include short stature, microcephaly, abnormalities of skull shape, and seizures. Eight variants (2 frameshift, 1 nonsense, 3 splice, and 2 missense) that have been reported in eight probands in four publications (PMIDs: 25363768, 29861108, 33323470, 34821460) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants occur primarily *de novo* but can be inherited from mildly affected parents. *TLK2* is highly constrained for both truncating and missense variants (gnomAD v4.1.0). The mechanism of pathogenicity appears to be loss of function, as most cases are heterozygous for truncating variants (PMID: 29861108). Reported missense variants cluster mainly in the C-terminal kinase domain; variants localized in this region show a reduction of kinase activity (PMID: 29955062). TLK2 activation requires dimerization through a coiled-coil domain, suggesting that inactive mutants could have a dominant negative effect (PMID: 29955062). This gene-disease relationship is also supported by experimental evidence, including *in vitro* functional assays of variants showing impaired kinase activity and decreased autophosphorylation (PMID: 29955062), and protein interactions with CHD7 and CHD8, which are also involved in neurodevelopmental disorders (PMID: 29955062). In summary, there is definitive evidence supporting the relationship between *TLK2* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 5, 2024 (SOP Version 11).

intellectual developmental disorder, autosomal dominant 57STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054837

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 57DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0054837

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 57AD

Manifestation: Craniofacial; Musculoskeletal; 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

Refs: 27479843; 29861108

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TLK2 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 173

Intellectual disability, autosomal dominant 57Total: 98

Inborn genetic diseasesTotal: 57

TLK2-related disorderTotal: 20

not specifiedTotal: 15

Neurodevelopmental disorderTotal: 3

Intellectual disabilityTotal: 2

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006852.6. 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			3 clinvar	21 clinvar		24
missense	1 clinvar	29 clinvar	145 clinvar	13 clinvar		188
nonsense	17 clinvar	15 clinvar	2 clinvar			34
start loss						0
frameshift	18 clinvar	6 clinvar	2 clinvar			26
splice donor/acceptor (+/-2bp)	12 clinvar	8 clinvar	10 clinvar			30
Total	48	58	162	34	0	302

Highest pathogenic variant AF is 0.000006578082

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 146 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006852.6	RefSeq	NP_006843.2	21	MANE Select
ENST00000346027.10	Ensembl	ENSP00000275780.7	21	MANE Select
NM_001284333.3	RefSeq	NP_001271262.1	22	Standard
NM_001284363.1	RefSeq	NP_001271292.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miRNA Regulation of DNA Damage Response
DNA Damage Response

Biological Process

regulation of chromatin assembly or disassembly
chromatin organization
protein phosphorylation
cellular response to DNA damage stimulus
cell cycle

Molecular Function

protein serine/threonine kinase activity
protein binding
ATP binding

Cellular Component

nucleus
intermediate filament
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000346027
Coding exons: 21
Length: 156824
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125741
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.49	148	401	0.369	0.0000217	4917
Missense (PolyPhen)		12	113.47	0.10575		1576
Synonymous	0.0259	145	145	0.997	0.00000802	1353
Loss of Function	6.62	2	55.0	0.0364	0.00000351	609

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine-protein kinase involved in the process of chromatin assembly and probably also DNA replication, transcription, repair, and chromosome segregation. Phosphorylates the chromatin assembly factors ASF1A AND ASF1B. Phosphorylation of ASF1A prevents its proteasome-mediated degradation, thereby enhancing chromatin assembly. Negative regulator of amino acid starvation-induced autophagy. {ECO:0000269|PubMed:10523312, ECO:0000269|PubMed:11470414, ECO:0000269|PubMed:12660173, ECO:0000269|PubMed:12955071, ECO:0000269|PubMed:20016786, ECO:0000269|PubMed:22354037, ECO:0000269|PubMed:9427565}.;

Recessive Scores

pRec: 0.0999

Intolerance Scores

LoFtool: 0.156
RVIS EVS: -0.27
RVIS percentile EVS: 34.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.451

Gene Damage Prediction

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