GeneBe

TRPC6

protein-coding

transient receptor potential cation channel subfamily C member 6, the group of Ankyrin repeat domain containing|MicroRNA protein coding host genes|Transient receptor potential cation channels

Gene summary

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. Activation of this channel occurs independently of protein kinase C and is not triggered by low levels of intracellular calcium. Defects in this gene are a cause of focal segmental glomerulosclerosis 2 (FSGS2). [provided by RefSeq, Mar 2009]

Previous symbols:
  • FSGS2

MANE transcript

NM_004621.6

Inheritance

AD

ClinVar variants

P:45U:281B:110

Top phenotype

Focal segmental glomerulosclerosis 2

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr11:101,451,564-101,872,562

External References & Databases

Ensembl (ENSG00000137672)NCBI Gene (7225)OMIM (603652)HGNC:12338GenCCUniProt (Q9Y210)AlphaFoldClinVar (TRPC6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~421.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

focal segmental glomerulosclerosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011390

Submitter: Labcorp Genetics (formerly Invitae)

focal segmental glomerulosclerosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011390

Submitter: Ambry Genetics

focal segmental glomerulosclerosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011390

Submitter: PanelApp Australia

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

Clinical Genomic Database (CGD)

Focal segmental glomerulosclerosis 2AD

Manifestation: Renal

Intervention: Renal

Rationale: The condition can involve renal failure, and early diagnosis may allow early management; Renal transplant has been described

Refs: 10200986; 15924139; 15879175; 21415313; 21511817; 21734084Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRPC6 variants in ClinVar

11 Conditions Cataloged
not providedTotal: 257
Focal segmental glomerulosclerosis 2Total: 207
Inborn genetic diseasesTotal: 96
TRPC6-related disorderTotal: 44
Prednisolone responseTotal: 32
not specifiedTotal: 24
Focal segmental glomerulosclerosisTotal: 11
Nephrotic syndromeTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004621.6. 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.

EffectPLPVUSLBBSum
synonymous
13
clinvar
75
clinvar
2
clinvar
 90
missense
4
clinvar
15
clinvar
252
clinvar
32
clinvar
1
clinvar
 304
nonsense
1
clinvar
7
clinvar
5
clinvar
 13
start loss
1
clinvar
 1
frameshift
1
clinvar
15
clinvar
4
clinvar
 20
splice donor/acceptor (+/-2bp)
2
clinvar
6
clinvar
 8
Total6392811073436

Highest pathogenic variant AF is 0.000011152112

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004621.6RefSeqNP_004612.213MANE Select
ENST00000344327.8EnsemblENSP00000340913.313MANE Select
NM_001439335.1RefSeqNP_001426264.111Standard
ENST00000348423.8EnsemblENSP00000343672.411Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Axon guidance - Homo sapiens (human)
  • cGMP-PKG signaling pathway - Homo sapiens (human)
  • Primary Focal Segmental Glomerulosclerosis FSGS
  • BDNF-TrkB Signaling
  • Signaling by GPCR

Biological Process

  • cation transport
  • manganese ion transport
  • positive regulation of cytosolic calcium ion concentration
  • single fertilization
  • aging

Molecular Function

  • actin binding
  • cation channel activity
  • calcium channel activity
  • protein binding
  • store-operated calcium channel activity

Cellular Component

  • cytoplasm
  • plasma membrane
  • integral component of plasma membrane
  • membrane
  • cation channel complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000344327
Coding exons
13
Length
420999
Individuals with no LoFs
125691
Homozygous LoFs
0
Heterozygous LoFs
57
Defined
125748
p
0.000227
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.123614940.7310.00002626173
Missense (PolyPhen)200311.530.641983838
Synonymous-0.6581871761.060.000009341715
Loss of Function3.311840.80.4410.00000207507

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000210.00018rare
Latino/Admixed American0.000380.00038rare
Ashkenazi Jewish00.0absent
East Asian0.000220.00022rare
Finnish00.0absent
European (Non-Finnish)0.000270.00026rare
South Asian0.000270.00020rare
Other0.000170.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Thought to form a receptor-activated non-selective calcium permeant cation channel (PubMed:19936226, PubMed:23291369). Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C (PubMed:26892346). Seems not to be activated by intracellular calcium store depletion. {ECO:0000269|PubMed:19936226, ECO:0000269|PubMed:23291369, ECO:0000269|PubMed:26892346}.;
Disease
DISEASE: Focal segmental glomerulosclerosis 2 (FSGS2) [MIM:603965]: A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. {ECO:0000269|PubMed:15879175, ECO:0000269|PubMed:15924139, ECO:0000269|PubMed:19458060, ECO:0000269|PubMed:19936226, ECO:0000269|PubMed:20798252, ECO:0000269|PubMed:21511817, ECO:0000269|PubMed:21734084, ECO:0000269|PubMed:22732337, ECO:0000269|PubMed:23014460, ECO:0000269|PubMed:23291369, ECO:0000269|PubMed:26892346}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.185

Intolerance Scores

LoFtool
0.225
RVIS EVS
-1.29
RVIS percentile EVS
5.08

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.577

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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