TCTN2

protein-coding

tectonic family member 2, the group of MKS complex|Tectonic proteins

Gene summary

This gene encodes a type I membrane protein that belongs to the tectonic family. Studies in mice suggest that this protein may be involved in hedgehog signaling, and essential for ciliogenesis. Mutations in this gene are associated with Meckel syndrome type 8. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

Previous symbols:

C12orf38

MANE transcript

NM_024809.5

Inheritance

ClinVar variants

P:84U:313B:165

Top phenotype

Joubert syndrome 24; Meckel syndrome 8

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr12:123,671,110-123,708,399

External References & Databases

Ensembl (ENSG00000168778)

Transcript & Mutation Effects

hg38 • Region Span ~37.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Joubert syndrome 24DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014724

Submitter: ClinGen

TCTN2 is located on chromosome 12 at 12q24.31 and encodes the Tectonic family member 2 type I membrane protein. The TCTN2 protein is a component of the tectonic-like complex which is localized at the transition zone of primary cilia and acts as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. TCTN2 was first reported in relation to Joubert Syndrome 24 in 2011 (Sang et al., PMID: 21565611). Joubert Syndrome is an autosomal recessive ciliopathy characterized by delays in psychomotor development in addition to congenital malformations of the brainstem appearing as agenesis or hypoplasia of the cerebellar vermis on brain imaging. TCTN2 has been noted to be associated with the following disease entities: Joubert Syndrome and Meckel Syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. We additionally found that observed phenotypic variability was representative of Meckel syndrome presenting as a severe manifestation on the phenotypic spectrum of Joubert Syndrome. Therefore, the following disease entities have been lumped into one disease entity, Joubert Syndrome 24 (OMIM:616654). A total of 6 variants (splice site, nonsense, and frameshift) that have been reported in 6 probands in 4 publications (PMID: Shaheen et al., 2011, PMID: 21462283; PMID: 21565611; Huppke et al., 2015, PMID: 25118024; Zhang et al., 2020, PMID: 32655147) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by expression studies, protein interaction studies and mouse models (Garcia-Gonzalo et al., 2011, PMID: 21725307; PMID: 21462283; PMID: 21565611). TCTN2 was shown to have significant levels of expression in mice in tissues commonly affected in Meckel Syndrome. Additionally, TCTN2 was shown to interact with another component of the tectonic-like complex and also implicated in Joubert Syndrome, TCTN1. The gene-disease relationship is supported by two mouse models, with a ciliopathy phenotype shown in one TCTN2 null mouse and further recapitulation of the human phenotype in another. In summary, TCTN2 is definitively associated with autosomal recessive Joubert Syndrome 24. 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 Syndromic Disorders GCEP on the meeting date 02.01.2023 (SOP Version 9.0).

Meckel syndrome, type 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013482

Submitter: LiferaOmics

ClinGen TCTN2–related Joubert syndrome 24 / Meckel syndrome 8 (AR) – Definitive – Approval: 2023 ClinGen curated TCTN2 – “Joubert syndrome 24” (lumped with Meckel syndrome 8, 613885) ClinGen Evidence Breakdown Genetic Evidence = 12.0 points (max reached; internal sum 14.0, capped at 12) Based on: • PMID: 21462283 • PMID: 21565611 • PMID: 25118024 • PMID: 32655147 Experimental Evidence = 5.0 points Based on: • PMID: 21462283 (expression) • PMID: 21725307 (protein interaction; mouse model) • PMID: 21565611 (mouse model) ClinGen Total = 17.0 (12 genetic + 5 experimental) Classification: Definitive Genetic Evidence – Our Cases Family 1 – one proband. Case-level (AR predicted null default; homozygous; consanguineous = −0.5 applied) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Family 2 – one proband. Case-level (AR predicted null; homozygous; consanguineous = −0.5) = 1.0; Segregation = 0; Case-control = 0 Family 2 total = 1.0 Family 3 – one proband. Case-level (AR predicted null 1.5; homozygous; consanguineous =−0.5) = 1.0; Segregation = 0; Case-control = 0 Family 3 total = 1.0 Family 4 – one proband. Case-level (AR predicted null; homozygous; non-consanguineous = no deduction) = 1.5; Segregation = 0; Case-control = 0 Family 4 total = 1.5 Family 5 – one proband. Case-level (AR predicted null; homozygous; consanguineous =−0.5) = 1.0; Segregation = 0; Case-control = 0 Family 5 total = 1.0 Our Case Total = 5.5 / 12 Updated Total Genetic Evidence (ClinGen + Our Cases) ClinGen genetic evidence: 12.0 (cap reached) Our additional cases: +5.5 Updated genetic total = 12.0 (cap maintained) Experimental Evidence (unchanged from ClinGen) ClinGen experimental evidence = 5.0 Our additional experimental evidence = 0 Updated Overall Score Genetic evidence = 12.0 Experimental evidence = 5.0 Updated total = 17.0

Joubert syndrome 24STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014724

Submitter: G2P

Meckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

Joubert syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Joubert syndrome 24STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014724

Submitter: Labcorp Genetics (formerly Invitae)

Joubert syndrome 24MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014724

Submitter: Ambry Genetics

Meckel syndrome, type 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013482

Submitter: PanelApp Australia

Joubert syndrome 24STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014724

Submitter: PanelApp Australia

Joubert syndrome 24DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014724

Submitter: Natera

Clinical Genomic Database (CGD)

Joubert syndrome 24; Meckel syndrome 8AR

Manifestation: Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic; Renal

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: The conditions may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveilMMABlance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial

Refs: 20301500; 21462283; 21565611; 25118024

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TCTN2 variants in ClinVar

12 Conditions Cataloged

Joubert syndromeTotal: 531

Meckel-Gruber syndromeTotal: 526

Joubert syndrome 24Total: 185

Meckel syndrome, type 8Total: 182

not providedTotal: 121

Inborn genetic diseasesTotal: 118

not specifiedTotal: 90

TCTN2-related disorderTotal: 36

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024809.5. 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			8 clinvar	148 clinvar	1 clinvar	157
missense		6 clinvar	293 clinvar	15 clinvar	1 clinvar	315
nonsense	12 clinvar	11 clinvar	2 clinvar			25
start loss						0
frameshift	12 clinvar	21 clinvar	3 clinvar			36
splice donor/acceptor (+/-2bp)	1 clinvar	21 clinvar	7 clinvar			29
Total	25	59	313	163	2	562

Highest pathogenic variant AF is 0.000058862675

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024809.5	RefSeq	NP_079085.2	18	MANE Select
ENST00000303372.7	Ensembl	ENSP00000304941.5	18	MANE Select
NM_001143850.3	RefSeq	NP_001137322.1	18	Standard
NM_001410989.1	RefSeq	NP_001397918.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Anchoring of the basal body to the plasma membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

smoothened signaling pathway
cilium assembly
ciliary basal body-plasma membrane docking

Cellular Component

cytoplasm
cytoskeleton
integral component of membrane
MKS complex
ciliary membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000303372
Coding exons: 18
Length: 37289
Individuals with no LoFs: 125661
Homozygous LoFs: 0
Heterozygous LoFs: 87
Defined: 125748
p: 0.000346

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.237	367	380	0.966	0.0000211	4550
Missense (PolyPhen)		68	78.949	0.86132		989
Synonymous	-0.655	161	151	1.07	0.00000962	1347
Loss of Function	1.60	27	37.6	0.718	0.00000192	430

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00080	0.00080	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00036	0.00036	rare
South Asian	0.00049	0.00046	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Required for hedgehog signaling transduction (By similarity). {ECO:0000250}.;
Disease: DISEASE: Meckel syndrome 8 (MKS8) [MIM:613885]: A disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. {ECO:0000269|PubMed:21462283}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 24 (JBTS24) [MIM:616654]: A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. {ECO:0000269|PubMed:21565611, ECO:0000269|PubMed:25118024}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.113
RVIS EVS: -0.82
RVIS percentile EVS: 11.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.115

Gene Damage Prediction

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