Human Gene Module / Chromosome 11 / TRPC6

TRPC6Transient receptor potential cation channel, subfamily C, member 6

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
19 / 0
EAGLE Score
7.2
Moderate Learn More
Aliases
TRPC6, FSGS2,  TRP6
Associated Syndromes
-
Chromosome Band
11q22.1
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Functional
Relevance to Autism

A de novo balanced translocation [t(3;11)(p21;q22)] disrupting the TRPC6 gene was identified in an 8-year-old male proband presenting with non-syndromic autism; further functional studies using patient-specific iPSC-derived neuronal cells and mouse models demonstrated that TRPC6 reduction or haploinsufficiency resulted in altered neuronal development, morphology, and function (Griesi-Oliveira et al., 2014).

Molecular Function

The protein encoded by this gene forms a receptor-activated calcium channel in the cell membrane. The channel is activated by diacylglycerol and is thought to be under the control of a phosphatidylinositol second messenger system. Defects in this gene are a cause of focal segmental glomerulosclerosis 2 (FSGS2) [MIM:603965].

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TRPC6 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Evidence for a supportive role of classical transient receptor potential 6 (TRPC6) in the exploration behavior of mice Beis D , et al. (2010) No -
2 Primary Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons Griesi-Oliveira K , et al. (2014) Yes -
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Support - Palacios-Muñoz A et al. (2022) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Shin KC et al. (2023) Yes -
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.222G>C p.Glu74Asp missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.70C>T p.Arg24Trp missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1293+2T>C - splice_site_variant Familial Maternal - 35501408 Palacios-Muñoz A et al. (2022)
c.7C>T p.Gln3Ter stop_gained Familial Paternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.139C>G p.Pro47Ala missense_variant Familial Paternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.620A>C p.Tyr207Ser missense_variant Familial Maternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.1057C>T p.Leu353Phe missense_variant Familial Paternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.1316C>G p.Pro439Arg missense_variant Familial Paternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.1396G>A p.Glu466Lys missense_variant Familial Paternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.1679C>T p.Ala560Val missense_variant Familial Maternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.2385C>G p.Phe795Leu missense_variant Familial Maternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.2424G>T p.Lys808Asn missense_variant Familial Maternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.2T>A p.Met1? initiator_codon_variant Familial Maternal Simplex 25385366 Griesi-Oliveira K , et al. (2014)
c.1208del p.Met403ArgfsTer33 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1073dup p.His358GlnfsTer14 frameshift_variant Familial Maternal - 35501408 Palacios-Muñoz A et al. (2022)
c.140del p.Pro47ArgfsTer33 frameshift_variant Unknown Not maternal - 35501408 Palacios-Muñoz A et al. (2022)
c.1204_1206delinsCC p.Thr402ProfsTer34 frameshift_variant Familial Maternal - 35501408 Palacios-Muñoz A et al. (2022)
c.177_178insATCTGACAACAGACTGGCTCACCGG p.Ser60IlefsTer2 frameshift_variant Familial Paternal - 35501408 Palacios-Muñoz A et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo balanced translocation [t(3;11)(p21;q22)] disrupting the TRPC6 gene was identified in an 8-year-old male proband presenting with non-syndromic autism; further functional studies using patient-specific iPSC-derived neuronal cells and mouse models demonstrated that TRPC6 reduction or haploinsufficiency resulted in altered neuronal development, morphology, and function (PMID 25385366). In a previous publication, TRPC6-deficient mice had been shown to display reduced exploratory behavior (PMID 21059368). Genetic sequencing of TRPC6 in 1041 ASD individuals from the Simons Simplex Collection and 2872 controls in PMID 25385366 identified significantly more nonsynonymous mutations in cases compared to controls (10/1041 cases versus 1/942 controls; P = 0.013), and loss-of-function mutations in TRPC6 showing incomplete penetrance with ASD were observed in two cases.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo balanced translocation [t(3;11)(p21;q22)] disrupting the TRPC6 gene was identified in an 8-year-old male proband presenting with non-syndromic autism; further functional studies using patient-specific iPSC-derived neuronal cells and mouse models demonstrated that TRPC6 reduction or haploinsufficiency resulted in altered neuronal development, morphology, and function (PMID 25385366). In a previous publication, TRPC6-deficient mice had been shown to display reduced exploratory behavior (PMID 21059368). Genetic sequencing of TRPC6 in 1041 ASD individuals from the Simons Simplex Collection and 2872 controls in PMID 25385366 identified significantly more nonsynonymous mutations in cases compared to controls (10/1041 cases versus 1/942 controls; P = 0.013), and loss-of-function mutations in TRPC6 showing incomplete penetrance with ASD were observed in two cases.

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo balanced translocation [t(3;11)(p21;q22)] disrupting the TRPC6 gene was identified in an 8-year-old male proband presenting with non-syndromic autism; further functional studies using patient-specific iPSC-derived neuronal cells and mouse models demonstrated that TRPC6 reduction or haploinsufficiency resulted in altered neuronal development, morphology, and function (PMID 25385366). In a previous publication, TRPC6-deficient mice had been shown to display reduced exploratory behavior (PMID 21059368). Genetic sequencing of TRPC6 in 1041 ASD individuals from the Simons Simplex Collection and 2872 controls in PMID 25385366 identified significantly more nonsynonymous mutations in cases compared to controls (10/1041 cases versus 1/942 controls; P = 0.013), and loss-of-function mutations in TRPC6 showing incomplete penetrance with ASD were observed in two cases.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2014
icon
3

Increased from to 3

Description

A de novo balanced translocation [t(3;11)(p21;q22)] disrupting the TRPC6 gene was identified in an 8-year-old male proband presenting with non-syndromic autism; further functional studies using patient-specific iPSC-derived neuronal cells and mouse models demonstrated that TRPC6 reduction or haploinsufficiency resulted in altered neuronal development, morphology, and function (PMID 25385366). In a previous publication, TRPC6-deficient mice had been shown to display reduced exploratory behavior (PMID 21059368). Genetic sequencing of TRPC6 in 1041 ASD individuals from the Simons Simplex Collection and 2872 controls in PMID 25385366 identified significantly more nonsynonymous mutations in cases compared to controls (10/1041 cases versus 1/942 controls; P = 0.013), and loss-of-function mutations in TRPC6 showing incomplete penetrance with ASD were observed in two cases.

Krishnan Probability Score

Score 0.50539006678127

Ranking 1908/25841 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 0.0045641050533557

Ranking 10670/18225 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 0.89115375773834

Ranking 5603/18665 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
Larsen Cumulative Evidence Score

Score 40

Ranking 48/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.23994777027222

Ranking 3624/20870 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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