SLC16A2
protein-codingsolute carrier family 16 member 2, the group of Solute carrier family 16
Gene summary
This gene encodes an integral membrane protein that functions as a transporter of thyroid hormone. The encoded protein facilitates the cellular importation of thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and diidothyronine (T2). This gene is expressed in many tissues and likely plays an important role in the development of the central nervous system. Loss of function mutations in this gene are associated with psychomotor retardation in males while females exhibit no neurological defects and more moderate thyroid-deficient phenotypes. This gene is subject to X-chromosome inactivation. Mutations in this gene are the cause of Allan-Herndon-Dudley syndrome. [provided by RefSeq, Mar 2012]
- DXS128
- AHDS
- MRX22
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~112.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010354
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010354
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010354
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010354
Submitter: ClinGen
*SLC16A2* was first reported in relation to X-linked Allan-Herndon-Dudley syndrome in 2004 (Dumitrescu et al., PMID: 14661163). Affected males show high serum 3,3',5-triiodothyronine (T3) concentration and low serum 3,3',5'-triiodothyronine (reverse T3) concentration, along with severe intellectual disability, infantile hypotonia, progressive spastic quadriplegia, and joint contractures. While heterozygous female carriers do not manifest psychomotor abnormalities, they have intermediate thyroid test abnormalities between affected and normal individuals. Eleven variants (missense, nonsense, frameshift), either familial or *de novo*, that have been reported in 11 probands in six publications (PMIDs: 14661163, 15488219, 15889350, 17899191, 19194886, 20713192) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. To date, 33 unique variants within *SLC16A2* have been classified as pathogenic in ClinVar. This gene-disease relationship is also supported by patient-derived neural cells and a chicken model, although mouse models do not show apparent neurological phenotypes (not curated here). In summary, there is definitive evidence supporting the relationship between *SLC16A* and X-linked Allan-Herndon-Dudley syndrome. 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 August 9, 2018 (SOP Version 5).
Inheritance Pattern: XL
Disease ID:MONDO:0010354
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic
Intervention: Endocrine; Obstetric
Rationale: In affected males, treatment with thyroid hormone has not been described as affecting the neurologic phenotype, but heterozygous women may benefit from monitoring and levothyroxine treatment during pregnancy in order to prevent fetal/neonatal hypothyroidism (regardless of fetal variant status)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC16A2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006517.5. 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 | 1 | 14 | 64 | 11 | 90 | |
| missense | 10 | 27 | 171 | 35 | 8 | 251 |
| nonsense | 21 | 4 | 25 | |||
| start loss | 2 | 2 | ||||
| frameshift | 26 | 13 | 1 | 40 | ||
| splice donor/acceptor (+/-2bp) | 7 | 3 | 7 | 17 | ||
| Total | 66 | 48 | 193 | 99 | 19 | 425 |
Highest pathogenic variant AF is 0.0000049561504
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006508.2 | 6 | MANE Select | |
| Ensembl | ENSP00000465734.1 | 6 | MANE Select | |
| Ensembl | ENSP00000466213.1 | 4 | Standard | |
| Ensembl | ENSP00000490445.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slc16a2 | Danio rerio | Structure: Rohon-Beard neuron Quality: has fewer parts of type abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Thyroid hormone signaling pathway - Homo sapiens (human)
- Angiopoietin Like Protein 8 Regulatory Pathway
- Tyrosine metabolism
- Transport of vitamins, nucleosides, and related molecules
- SLC-mediated transmembrane transport
Biological Process
- monocarboxylic acid transport
- sodium-independent organic anion transport
- transmembrane transport
- thyroid hormone transport
Molecular Function
- transporter activity
- monocarboxylic acid transmembrane transporter activity
- symporter activity
- thyroid hormone transmembrane transporter activity
Cellular Component
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000587091
- Coding exons
- 6
- Length
- 112668
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.38 | 126 | 227 | 0.555 | 0.0000182 | 3504 |
| Missense (PolyPhen) | 25 | 90.967 | 0.27483 | 1405 | ||
| Synonymous | 0.889 | 81 | 91.8 | 0.882 | 0.00000727 | 1124 |
| Loss of Function | 3.39 | 0 | 13.4 | 0.00 | 0.00000100 | 202 |
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 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Very active and specific thyroid hormone transporter. Stimulates cellular uptake of thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and diidothyronine. Does not transport Leu, Phe, Trp or Tyr. {ECO:0000269|PubMed:23550058, ECO:0000269|PubMed:26426690}.;
Recessive Scores
- pRec
- 0.215
Intolerance Scores
- RVIS EVS
- 0.1
- RVIS percentile EVS
- 61.49
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.187
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |