Human Gene Module / Chromosome 9 / TRPM6

TRPM6transient receptor potential cation channel subfamily M member 6

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
13 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
9q21.13
Associated Disorders
-
Relevance to Autism

De novo variants in the TRPM6 gene have been identified in ASD probands, including two de novo missense variants (p.Ala641Glu and p.Thr2011Pro) in probands from the Simons Simplex Collection and a de novo nonsense variant in a proband from the MSSNG cohort (Iossifov et al., 2014; Yuen et al., 2016). Functional assessment of the two ASD-associated missense variants originally identified in probands from the Simons Simplex Collection in Drosophila using a rescue-based strategy in Macrogliese et al., 2022 demonstrated that both mutations resulted in a reduced ability to rescue TG4 lethality in humanized flies compared with reference animals, consistent with a loss-of-function effect.

Molecular Function

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. Biallelic variants in this gene are associated with hypomagnesemia with secondary hypocalcemia (OMIM 602014); seizures have been observed in affected individuals.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TRPM6 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Recent Recommendation - Marcogliese PC et al. (2022) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1293+892G>C - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.2376+900C>G - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.5761+621G>A - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.4907-1221C>T - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.4770+1999A>G - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.137+2708C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.3210-233C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.5920+305C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.5765T>A p.Leu1922Ter stop_gained De novo - Simplex 27525107 Yuen RK et al. (2016)
c.137+5G>A - splice_region_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1922C>A p.Ala641Glu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.6031A>C p.Thr2011Pro missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2451T>C p.Gly817%3D synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49004673872124

Ranking 6292/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.58834497319285

Ranking 5051/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.60104275638304

Ranking 712/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.68841617580581

Ranking 20309/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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