TM2D1

Chr 1

TM2 domain containing 1

Also known as: BBP

NCBI Gene: 83941 ENSG00000162604 UniProt: Q9BX74 OMIM: 610080

The protein encoded by TM2D1 is a beta-amyloid peptide-binding protein that contains structural domains similar to G protein-coupled receptors and may participate in amyloid-beta-induced apoptosis. This gene is extremely intolerant to loss-of-function mutations (pLI = 0.999), suggesting that variants in TM2D1 would likely cause severe developmental disorders, though specific pediatric phenotypes have not yet been established. The inheritance pattern for TM2D1-related disorders has not been determined.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a beta-amyloid peptide-binding protein. It contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily and known to be important in heterotrimeric G protein activation. Beta-amyloid peptide has been established to be a causative factor in neuron death and the consequent diminution of cognitive abilities observed in Alzheimer's disease. This protein may be a target of neurotoxic beta-amyloid peptide, and may mediate cellular vulnerability to beta-amyloid peptide toxicity through a G protein-regulated program of cell death. Several transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.11

Clinical Summary— TM2D1

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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

31 VUS of 40 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?

1.11LOEUF

pLI 0.000

Z-score 1.27

OE 0.62 (0.36–1.11)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.13Z-score

OE missense 0.97 (0.84–1.12)

132 obs / 136.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.36–1.11)

0≤0.351.4

Missense OE?0.97 (0.84–1.12)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 8 / 12.9Missense obs/exp: 132 / 136.2Syn Z: -0.34

This gene — mechanism propensity

0.6551th %ile

GOF

0.6834th %ile

LOF

0.2776th %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

40 submitted variants in ClinVar

ClinVar

Classification Summary

VUS31

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	31	31
Likely Benign	0	0
Benign	0	0
Total	31	31

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap TM2D1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →