TRPM6
protein-codingtransient receptor potential cation channel subfamily M member 6, the group of Transient receptor potential cation channels
Gene summary
This gene is predominantly expressed in the kidney and colon, and encodes a protein containing an ion channel domain and a protein kinase domain. It is crucial for magnesium homeostasis, and plays an essential role in epithelial magnesium transport and in the active magnesium absorption in the gut and kidney. Mutations in this gene are associated with hypomagnesemia with secondary hypocalcemia. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Apr 2010]
- HOMG
- HSH
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~165.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011176
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011176
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0011176
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011176
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Gastrointestinal
Intervention: Gastrointestinal
Rationale: Individuals typically present in infancy with manifestations of electrolyte imbalances (hypomagnesemia and consequent hypocalcemia) , which may result in death or severe neurologic impairment such that immediate magnesium administration can be effective in the acute period, though individuals require chronic high-dose oral magnesium supplementation
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TRPM6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017662.5. 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 | 24 | 146 | 3 | 173 | ||
| missense | 2 | 2 | 418 | 34 | 4 | 460 |
| nonsense | 12 | 13 | 2 | 27 | ||
| start loss | 0 | |||||
| frameshift | 14 | 17 | 3 | 34 | ||
| splice donor/acceptor (+/-2bp) | 6 | 10 | 2 | 18 | ||
| Total | 34 | 42 | 449 | 180 | 7 | 712 |
Highest pathogenic variant AF is 0.000019707022
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060132.3 | 39 | MANE Select | |
| Ensembl | ENSP00000354006.1 | 39 | MANE Select | |
| RefSeq | NP_001170781.1 | 39 | Standard | |
| RefSeq | NP_001170782.1 | 39 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mineral absorption - Homo sapiens (human)
- Stimuli-sensing channels
- Ion channel transport
- Transport of small molecules
- TRP channels
Biological Process
- protein phosphorylation
- response to toxic substance
- protein tetramerization
- calcium ion transmembrane transport
Molecular Function
- protein serine/threonine kinase activity
- calcium channel activity
- protein binding
- ATP binding
- metal ion binding
Cellular Component
- plasma membrane
- integral component of membrane
- apical plasma membrane
- brush border membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000360774
- Coding exons
- 39
- Length
- 165600
- Individuals with no LoFs
- 125685
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 63
- Defined
- 125748
- p
- 0.000251
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.61 | 885 | 1.03e+3 | 0.859 | 0.0000550 | 13362 |
| Missense (PolyPhen) | 244 | 327.76 | 0.74444 | 4428 | ||
| Synonymous | -1.40 | 415 | 380 | 1.09 | 0.0000213 | 3737 |
| Loss of Function | 6.37 | 38 | 110 | 0.345 | 0.00000593 | 1315 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00032 | 0.00031 | rare |
| South Asian | 0.00033 | 0.00029 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Essential ion channel and serine/threonine-protein kinase. Crucial for magnesium homeostasis. Has an important role in epithelial magnesium transport and in the active magnesium absorption in the gut and kidney. Isoforms of the type M6-kinase lack the ion channel region.;
Recessive Scores
- pRec
- 0.174
Intolerance Scores
- LoFtool
- 0.660
- RVIS EVS
- -0.58
- RVIS percentile EVS
- 18.72
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.100
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |