TPSB2

Chr 16

tryptase beta 2

Also known as: TPS2, tryptaseB, tryptaseC

NCBI Gene: 64499 ENSG00000197253 UniProt: P20231 OMIM: 191081

Tryptase beta-2 is a serine protease that serves as the major neutral protease in mast cells and is secreted during mast cell degranulation, potentially playing a role in innate immunity. This gene is extremely tolerant to loss-of-function variants (LOEUF 1.898), and mutations in TPSB2 are associated with hereditary alpha tryptasemia, an autosomal dominant condition characterized by elevated baseline serum tryptase levels and symptoms including flushing, pruritus, gastrointestinal issues, and allergic-type reactions. The condition typically manifests with systemic symptoms affecting multiple organ systems including skin, gastrointestinal tract, and cardiovascular system.

OMIM ResearchSummary from RefSeq, UniProt

Tryptases comprise a family of trypsin-like serine proteases, the peptidase family S1. Tryptases are enzymatically active only as heparin-stabilized tetramers, and they are resistant to all known endogenous proteinase inhibitors. Several tryptase genes are clustered on chromosome 16p13.3. These genes are characterized by several distinct features. They have a highly conserved 3' UTR and contain tandem repeat sequences at the 5' flank and 3' UTR which are thought to play a role in regulation of the mRNA stability. These genes have an intron immediately upstream of the initiator Met codon, which separates the site of transcription initiation from protein coding sequence. This feature is characteristic of tryptases but is unusual in other genes. The alleles of this gene exhibit an unusual amount of sequence variation, such that the alleles were once thought to represent two separate genes, beta II and beta III. Beta tryptases appear to be the main isoenzymes expressed in mast cells, whereas in basophils, alpha-tryptases predominate. Tryptases have been implicated as mediators in the pathogenesis of asthma and other allergic and inflammatory disorders. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.90

Clinical Summary— TPSB2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

36 VUS of 53 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.90LOEUF

pLI 0.000

Z-score -0.96

OE 1.36 (0.84–1.90)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.04Z-score

OE missense 1.59 (1.39–1.82)

149 obs / 93.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.36 (0.84–1.90)

0≤0.351.4

Missense OE?1.59 (1.39–1.82)

0≤0.61.4

Synonymous OE?1.60

0≤1.21.6

LoF obs/exp: 11 / 8.1Missense obs/exp: 149 / 93.5Syn Z: -3.10

This gene — mechanism propensity

0.6841th %ile

GOF

0.72top 25%

LOF

0.3162th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

53 submitted variants in ClinVar

ClinVar

Classification Summary

VUS36

Likely Benign9

Benign2

Conflicting1

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	36	0	0	36
Likely Benign	0	5	0	4	9
Benign	0	2	0	0	2
Conflicting	—				1
Total	0	43	0	4	48

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

48 pathogenic / likely-pathogenic (of 66) ClinVar copy-number / structural variants overlap TPSB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →