TPCN2

Chr 11

two pore segment channel 2

Also known as: SHEP10, TPC2

NCBI Gene: 219931 ENSG00000162341 UniProt: Q8NHX9

This protein is a lysosomal and endosomal ion channel that conducts calcium and sodium ions in response to NAADP and PI(3,5)P2, regulating organellar pH homeostasis, membrane trafficking, and melanogenesis. Mutations cause skin/hair/eye pigmentation 10, characterized by blond versus brown hair pigmentation differences. The gene shows high constraint against loss-of-function variants (pLI near 0, LOEUF 0.691), suggesting intolerance to protein-truncating mutations.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.69

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.000

Z-score 3.30

OE 0.49 (0.35–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.45Z-score

OE missense 0.94 (0.87–1.02)

412 obs / 438.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.35–0.69)

0≤0.351.4

Missense OE?0.94 (0.87–1.02)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 24 / 48.9Missense obs/exp: 412 / 438.6Syn Z: 0.35

Background carrier burden — how many people carry a rare variant somewhere in TPCN2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 37

1,113 rare PASS variants

Rare truncating (LoF)

1 in 450

183 rare PASS variants

Rare synonymous (reference)

1 in 60

405 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TPCN2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 47	1 in 470
South Asian	~43k	1 in 38	1 in 740
Remaining (unassigned)	~30k	1 in 32	1 in 290
European (Finnish)	~27k	1 in 120	1 in 1,000
Admixed American	~22k	1 in 41	1 in 410
African / African American	~21k	1 in 38	1 in 520
East Asian	~20k	1 in 41	1 in 380
Ashkenazi Jewish	~13k	1 in 220	≈ 1 in 3,400
Middle Eastern	~2,884	1 in 58	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 24 of 25 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 25.? see exons ↓