TELO2

protein-coding

telomere maintenance 2, the group of Armadillo like helical domain containing|TTT complex

Gene summary

This gene encodes a protein that functions as an S-phase checkpoint protein in the cell cycle. The protein may also play a role in DNA repair.[provided by RefSeq, Mar 2009]

MANE transcript

NM_016111.4

Inheritance

ClinVar variants

P:39U:260B:234

Top phenotype

You-Hoover-Fong syndrome

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr16:1,493,344-1,510,457

External References & Databases

Ensembl (ENSG00000100726)

Transcript & Mutation Effects

hg38 • Region Span ~17.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

TELO2-related intellectual disability-neurodevelopmental disorderSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014848

Submitter: Orphanet

TELO2-related intellectual disability-neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014848

Submitter: G2P

TELO2-related intellectual disability-neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014848

Submitter: Labcorp Genetics (formerly Invitae)

TELO2-related intellectual disability-neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014848

Submitter: ClinGen

*TELO2* was first reported in relation to autosomal recesssive syndromic intellectual disability and neurodevelopmental disorder in 2016 (You et al., PMID:27132593). *TELO2*-related intellectual disability-neurodevelopmental disorder (You-Hoover-Fong syndrome) is characterized by delayed global development, microcephaly, abnormal balance, and a movement disorder. At least 11 variants (including missense, nonsense, frameshift, exonic deletion) have been reported (PMID: 28944240, 33307281, 32940098). Evidence supporting this gene-disease relationship includes case-level and experimental data. In summary, there is definitive evidence supporting the relationship between *TELO2* and *TELO2*-related intellectual disability-neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 1, 2022 (SOP Version 9).

TELO2-related intellectual disability-neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014848

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

You-Hoover-Fong syndromeAR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 27132593

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TELO2 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 498

Inborn genetic diseasesTotal: 189

TELO2-related intellectual disability-neurodevelopmental disorderTotal: 42

not specifiedTotal: 30

TELO2-related disorderTotal: 25

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016111.4. 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			5 clinvar	170 clinvar	10 clinvar	185
missense	1 clinvar	9 clinvar	246 clinvar	44 clinvar	10 clinvar	310
nonsense	1 clinvar	4 clinvar	2 clinvar			7
start loss		1 clinvar				1
frameshift	10 clinvar	4 clinvar	1 clinvar			15
splice donor/acceptor (+/-2bp)		9 clinvar	6 clinvar			15
Total	12	27	260	214	20	533

Highest pathogenic variant AF is 0.00018075545

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 84 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016111.4	RefSeq	NP_057195.2	20	MANE Select
ENST00000262319.11	Ensembl	ENSP00000262319.6	20	MANE Select
NM_001351846.2	RefSeq	NP_001338775.1	20	Standard
ENST00000497339.6	Ensembl	ENSP00000456383.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
mTOR signaling pathway - Homo sapiens (human)
Steatosis AOP

Biological Process

telomere maintenance
regulation of TOR signaling
protein stabilization
positive regulation of protein serine/threonine kinase activity
positive regulation of TORC1 signaling

Molecular Function

protein binding
protein kinase binding
protein-containing complex scaffold activity
telomeric DNA binding
protein-containing complex binding

Cellular Component

nuclear chromosome, telomeric region
nucleus
cytoplasm
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262319
Coding exons: 20
Length: 17114
Individuals with no LoFs: 125677
Homozygous LoFs: 0
Heterozygous LoFs: 68
Defined: 125745
p: 0.000270

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.367	568	544	1.04	0.0000379	5237
Missense (PolyPhen)		105	117.32	0.89499		1314
Synonymous	-1.95	294	254	1.16	0.0000184	1838
Loss of Function	1.93	27	40.2	0.672	0.00000209	424

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00028	0.00025	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00098	0.00092	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00029	0.00027	rare
South Asian	0.00030	0.00029	rare
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulator of the DNA damage response (DDR). Part of the TTT complex that is required to stabilize protein levels of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC). Together with the TTT complex and HSP90 may participate in the proper folding of newly synthesized PIKKs. Promotes assembly, stabilizes and maintains the activity of mTORC1 and mTORC2 complexes, which regulate cell growth and survival in response to nutrient and hormonal signals. May be involved in telomere length regulation. {ECO:0000269|PubMed:12670948, ECO:0000269|PubMed:20810650}.;
Disease: DISEASE: You-Hoover-Fong syndrome (YHFS) [MIM:616954]: A syndrome characterized by severe global developmental delay, intellectual disability, dysmorphic facial features, microcephaly, abnormal movements, congenital heart disease comprising developmental abnormalities of the great vessels, and abnormal auditory and visual function. The transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:27132593}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.217
RVIS EVS: 0.42
RVIS percentile EVS: 76.68

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.643

Gene Damage Prediction

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