TCF7L2

Chr 10AD

transcription factor 7 like 2

Also known as: TCF-4, TCF4

NCBI Gene: 6934 ENSG00000148737 UniProt: Q9NQB0 OMIM: 602228

The TCF7L2 protein is a transcription factor that participates in Wnt signaling and regulates gene expression including MYC, playing essential roles in epithelial stem cell maintenance and glucose homeostasis. Mutations cause autosomal dominant susceptibility to type 2 diabetes mellitus. This gene is highly constrained against loss-of-function variants (pLI 0.995, LOEUF 0.273), indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a high mobility group (HMG) box-containing transcription factor that plays a key role in the Wnt signaling pathway. The protein has been implicated in blood glucose homeostasis. Genetic variants of this gene are associated with increased risk of type 2 diabetes. Several transcript variants encoding multiple different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.271 OMIM phenotype

Clinical Summary— TCF7L2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.995

Z-score 4.73

OE 0.12 (0.06–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.40Z-score

OE missense 0.64 (0.57–0.72)

227 obs / 354.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.27)

0≤0.351.4

Missense OE?0.64 (0.57–0.72)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 4 / 33.5Missense obs/exp: 227 / 354.0Syn Z: -2.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTCF7L2-related developmental disorderLOFAD

This gene — mechanism propensity

0.4587th %ile

GOF

0.3193th %ile

LOF

0.84top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.27

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.