TMEM216

protein-coding

transmembrane protein 216

Gene summary

This locus encodes a transmembrane domain-containing protein. Mutations at this locus have been associated with Meckel-Gruber Syndrome Type 2, and Joubert Syndrome 2, also known as Cerebello-oculorenal Syndrome 2. [provided by RefSeq, Aug 2010]

Previous symbols:

CORS2
MKS2

MANE transcript

NM_001173990.3

Inheritance

ClinVar variants

P:53U:82B:71

Top phenotype

Joubert syndrome 2; Meckel syndrome 2; Retinitis pigmentosa 98

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr11:61,392,393-61,398,866

External References & Databases

Ensembl (ENSG00000187049)

Transcript & Mutation Effects

hg38 • Region Span ~6.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ciliopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: PanelApp Australia

Joubert syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011963

Submitter: G2P

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

The *TMEM216* gene is located on chromosome 11 at q12.2 and encodes Transmembrane Protein 216. which is a tetraspan transmembrane protein containing four hydrophobic transmembrane domains. These proteins appear to regulate signaling and trafficking properties of other partner proteins, including Wnt receptors. It is expressed in a variety of tissues and organs, including the kidney. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism and/or inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity: autosomal recessive ciliopathies (MONDOID: 0005308). *TMEM216* was first reported in relation to autosomal recessive ciliopathies in 2010 (Enza et al., PMID: 20512146). Clinical presentations associated with *TMEM216* pathogenic variants include hypotonia, ataxia, psychomotor delay, irregular breathing pattern and oculomotor apraxia. Affected individuals may have multiorgan involvement, mainly retinal dystrophy, nephronophthisis, congenital liver fibrosis, occipital encephalocele and other posterior fossa defects, cystic dysplastic kidneys, hepatic bile duct proliferation and polydactyly. Pathogenicity is reported to be due to loss of function. 9 variants (missense, nonsense, and frameshift) have been reported in 69 probands in 4 publications (PMIDs: 20036350, 20512146, 36788019, 23351400) included in this curation. A total of 8.6/12 pts. genetic evidence was reached, considering case-level data and functional data. This gene-disease relationship is also supported by non-patient cells and non-human models. *TMEM216* deficiency induces ciliopathies in paramecia, zebra fish, and mice (PMIDs: 32163404, 32687549, 36533556, 38261656]. A total of 4.5/6 pts. for experimental evidence was reached. In summary, there is Definitive evidence supporting the relationship between *TMEM216* and autosomal recessive ciliopathies. 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 KCCD GCEP on the meeting date September 9th, 2024 (SOP Version 10).

Joubert syndrome with oculorenal defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009480

Submitter: Orphanet

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: Natera

Meckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

orofaciodigital syndrome type 6SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010176

Submitter: Orphanet

Joubert syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011963

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Joubert syndrome 2; Meckel syndrome 2; Retinitis pigmentosa 98AR

Manifestation: Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; 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: Some conditions may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial

Refs: 20036350; 20512146; 39191256

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM216 variants in ClinVar

12 Conditions Cataloged

Joubert syndromeTotal: 220

Joubert syndrome 2Total: 103

Meckel syndrome, type 2Total: 67

not providedTotal: 44

TMEM216-related disorderTotal: 33

not specifiedTotal: 29

Inborn genetic diseasesTotal: 22

CiliopathyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001173990.3. 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	67 clinvar		71
missense	2 clinvar	3 clinvar	67 clinvar	4 clinvar		76
nonsense	5 clinvar	4 clinvar	1 clinvar			10
start loss			5 clinvar			5
frameshift	8 clinvar	15 clinvar	1 clinvar			24
splice donor/acceptor (+/-2bp)	1 clinvar	15 clinvar	4 clinvar			20
Total	16	37	82	71	0	206

Highest pathogenic variant AF is 0.00014751713

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001173990.3	RefSeq	NP_001167461.1	5	MANE Select
ENST00000515837.7	Ensembl	ENSP00000440638.1	5	MANE Select
NM_001173991.3	RefSeq	NP_001167462.1	5	Standard
NM_001330285.2	RefSeq	NP_001317214.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tmem216	Danio rerio	Structure: whole organism Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

tmem216

Danio rerio

Structure: whole organism

Quality: decreased length

abnormal

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

cilium assembly
ciliary basal body-plasma membrane docking
non-motile cilium assembly

Molecular Function

protein binding

Cellular Component

cytosol
cytoskeleton
cilium
integral component of membrane
ciliary transition zone

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000515837
Coding exons: 5
Length: 7177
Individuals with no LoFs: 7894
Homozygous LoFs: 86544
Heterozygous LoFs: 30200
Defined: 124638
p: 0.748

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.491	66	78.2	0.844	0.00000397	911
Missense (PolyPhen)		26	27.714	0.93816		347
Synonymous	0.995	25	32.2	0.777	0.00000160	310
Loss of Function	0.880	5	7.62	0.656	4.07e-7	84

Population LoF Frequency

Population	CAF	p-value	Status
African	0.35	0.34	notable
Latino/Admixed American	0.86	0.81	notable
Ashkenazi Jewish	0.89	0.83	notable
East Asian	0.96	0.91	notable
Finnish	0.88	0.83	notable
European (Non-Finnish)	0.85	0.79	notable
South Asian	0.83	0.78	notable
Other	0.85	0.80	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition. {ECO:0000269|PubMed:22282472}.;
Disease: DISEASE: Joubert syndrome 2 (JBTS2) [MIM:608091]: 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 and renal disease. {ECO:0000269|PubMed:20036350, ECO:0000269|PubMed:20512146, ECO:0000269|PubMed:22282472, ECO:0000269|PubMed:22425360}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Meckel syndrome 2 (MKS2) [MIM:603194]: 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:20512146}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.921

Gene Damage Prediction

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