TRPV6

protein-coding

transient receptor potential cation channel subfamily V member 6, the group of Transient receptor potential cation channels|Ankyrin repeat domain containing

Gene summary

This gene encodes a member of a family of multipass membrane proteins that functions as calcium channels. The encoded protein contains N-terminal ankyrin repeats, which are required for channel assembly and regulation. Translation initiation for this protein occurs at a non-AUG start codon that is decoded as methionine. This gene is situated next to a closely related gene for transient receptor potential cation channel subfamily V member 5 (TRPV5). This locus has experienced positive selection in non-African populations, resulting in several non-synonymous codon differences among individuals of different genetic backgrounds. [provided by RefSeq, Feb 2015]

Previous symbols:

ECAC2

MANE transcript

NM_018646.6

Inheritance

AR, AD

ClinVar variants

P:26U:217B:81

Top phenotype

Hyperparathyroidism, transient neonatal

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr7:142,871,208-142,885,745

External References & Databases

Ensembl (ENSG00000165125)

Transcript & Mutation Effects

hg38 • Region Span ~14.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperparathyroidism, transient neonatalSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032591

Submitter: PanelApp Australia

neonatal severe primary hyperparathyroidismSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009397

Submitter: Orphanet

pancreatitisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0004982

Submitter: Ambry Genetics

hereditary chronic pancreatitisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: PanelApp Australia

intestinal hypomagnesemia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011176

Submitter: Labcorp Genetics (formerly Invitae)

hyperparathyroidism, transient neonatalSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032591

Submitter: G2P

hyperparathyroidism, transient neonatalMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032591

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hyperparathyroidism, transient neonatalAR

Manifestation: Musculoskeletal

Intervention: Musculoskeletal

Rationale: Individuals can present in early life with fractures, respiratory and feeding difficulties, and management with oral calcium has shown to be beneficial

Refs: 29861107

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRPV6 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 323

Inborn genetic diseasesTotal: 91

not specifiedTotal: 35

TRPV6-related disorderTotal: 27

Hyperparathyroidism, transient neonatalTotal: 22

Embryonic calcium dysregulationTotal: 1

Metaphyseal fracturesTotal: 1

Slender long boneTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018646.6. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	63 clinvar	9 clinvar	76
missense		8 clinvar	212 clinvar	8 clinvar	1 clinvar	229
nonsense	3 clinvar	3 clinvar				6
start loss						0
frameshift	8 clinvar	2 clinvar	1 clinvar			11
splice donor/acceptor (+/-2bp)		2 clinvar				2
Total	11	15	217	71	10	324

Highest pathogenic variant AF is 0.00008240029

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018646.6	RefSeq	NP_061116.5	15	MANE Select
ENST00000359396.9	Ensembl	ENSP00000352358.5	15	MANE Select
ENST00000431833.1	Ensembl	ENSP00000415917.1	2	Standard
ENST00000436401.1	Ensembl	ENSP00000411100.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
trpv6	Danio rerio	Structure: corpuscles of Stannius Quality: cellular quality abnormal

Gene / Model

Organism

Observed Phenotype

trpv6

Danio rerio

Structure: corpuscles of Stannius

Quality: cellular quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Salivary secretion - Homo sapiens (human)
Mineral absorption - Homo sapiens (human)
miR-targeted genes in lymphocytes - TarBase
Vitamin D Receptor Pathway
Stimuli-sensing channels

Biological Process

calcium ion transport
regulation of calcium ion-dependent exocytosis
response to calcium ion
calcium ion homeostasis
calcium ion transmembrane transport

Molecular Function

ion channel activity
calcium channel activity
protein binding
calmodulin binding
metal ion binding

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359396
Coding exons: 15
Length: 14552
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 55
Defined: 125748
p: 0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.38	365	447	0.816	0.0000280	4724
Missense (PolyPhen)		103	149.91	0.68707		1673
Synonymous	0.770	160	173	0.925	0.0000101	1453
Loss of Function	3.19	17	38.3	0.444	0.00000209	387

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.00052	0.00052	rare
Other	0.00052	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Calcium selective cation channel that mediates Ca(2+) uptake in various tissues, including the intestine (PubMed:11097838, PubMed:11278579, PubMed:11248124 PubMed:15184369, PubMed:23612980, PubMed:29258289). Important for normal Ca(2+) ion homeostasis in the body, including bone and skin (By similarity). The channel is activated by low internal calcium level, probably including intracellular calcium store depletion, and the current exhibits an inward rectification (PubMed:15184369). Inactivation includes both a rapid Ca(2+)- dependent and a slower Ca(2+)-calmodulin-dependent mechanism; the latter may be regulated by phosphorylation. In vitro, is slowly inhibited by Mg(2+) in a voltage-independent manner. Heteromeric assembly with TRPV5 seems to modify channel properties. TRPV5- TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating. {ECO:0000250|UniProtKB:Q91WD2, ECO:0000269|PubMed:11097838, ECO:0000269|PubMed:11248124, ECO:0000269|PubMed:11278579, ECO:0000269|PubMed:15184369, ECO:0000269|PubMed:23612980, ECO:0000269|PubMed:29258289}.;

Intolerance Scores

LoFtool: 0.351
RVIS EVS: -0.68
RVIS percentile EVS: 15.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.727

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium