TPCN2

protein-coding

two pore segment channel 2, the group of Two pore segment channels|MicroRNA protein coding host genes

Gene summary

This gene encodes a putative cation-selective ion channel with two repeats of a six-transmembrane-domain. The protein localizes to lysosomal membranes and enables nicotinic acid adenine dinucleotide phosphate (NAADP) -induced calcium ion release from lysosome-related stores. This ubiquitously expressed gene has elevated expression in liver and kidney. Two common nonsynonymous SNPs in this gene strongly associate with blond versus brown hair pigmentation.[provided by RefSeq, Dec 2009]

MANE transcript

NM_139075.4

Inheritance

ClinVar variants

P:1U:148B:22

Top phenotype

Skin/hair/eye pigmentation, variation in, 10

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr11:69,048,932-69,136,316

External References & Databases

Ensembl (ENSG00000162341)

Transcript & Mutation Effects

hg38 • Region Span ~87.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

albinismLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0043209

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Skin/hair/eye pigmentation, variation in, 10AD

Manifestation: Dermatologic

Intervention: General

Rationale: The condition may not be clinically relevant

Comments: Variants may be involved in sun sensitivity

Refs: 18488028

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TPCN2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 154

not providedTotal: 12

TPCN2-related conditionTotal: 5

SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 10Total: 2

Marfanoid habitus and intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_139075.4. 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	8 clinvar	4 clinvar	16
missense		1 clinvar	135 clinvar	7 clinvar	3 clinvar	146
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	0	1	148	15	7	171

Highest pathogenic variant AF is 0.0000024784345

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_139075.4	RefSeq	NP_620714.2	25	MANE Select
ENST00000294309.8	Ensembl	ENSP00000294309.3	25	MANE Select
ENST00000542467.1	Ensembl	ENSP00000445551.1	18	Standard
ENST00000542467.2	Ensembl	ENSP00000445551.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tpcn2	Danio rerio	Structure: slow muscle cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

tpcn2

Danio rerio

Structure: slow muscle cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pancreatic secretion - Homo sapiens (human)
VEGFA-VEGFR2 Signaling Pathway
Ebola Virus Pathway on Host
Ebola Virus Pathway on Host
Stimuli-sensing channels

Biological Process

cellular calcium ion homeostasis
smooth muscle contraction
lysosome organization
regulation of autophagy
calcium-mediated signaling

Molecular Function

voltage-gated calcium channel activity
protein binding
protein kinase binding
identical protein binding
NAADP-sensitive calcium-release channel activity

Cellular Component

lysosome
lysosomal membrane
endosome membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000294309
Coding exons: 25
Length: 41708
Individuals with no LoFs: 125659
Homozygous LoFs: 0
Heterozygous LoFs: 89
Defined: 125748
p: 0.000354

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.451	412	439	0.939	0.0000278	4827
Missense (PolyPhen)		151	180.17	0.83812		1886
Synonymous	0.349	185	191	0.968	0.0000126	1528
Loss of Function	3.30	24	48.9	0.491	0.00000265	492

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00056	0.00055	rare
Latino/Admixed American	0.00049	0.00049	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00038	0.00036	rare
South Asian	0.00026	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Nicotinic acid adenine dinucleotide phosphate (NAADP) receptor that may function as one of the major voltage-gated Ca(2+) channels (VDCC) across the lysosomal membrane. May be involved in smooth muscle contraction. {ECO:0000269|PubMed:19387438, ECO:0000269|PubMed:19620632}.;

Recessive Scores

pRec: 0.130

Intolerance Scores

LoFtool: 0.0941
RVIS EVS: -0.34
RVIS percentile EVS: 29.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.170

Gene Damage Prediction

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