TCF7L2

transcription factor 7 like 2, the group of TCF/LEF transcription factor family|Wnt enhanceosome complex

Basic information

Region (hg38): 10:112950246-113167678

Previous symbols: [ "TCF4" ]

Links

ENSG00000148737 ∙ NCBI:6934 ∙ OMIM:602228 ∙ HGNC:11641 ∙ Uniprot:Q9NQB0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital glaucoma (Limited), mode of inheritance: Unknown
• intellectual disability (Moderate), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TCF7L2 gene.

• not provided (77 variants)
• Inborn genetic diseases (27 variants)
• Autism (1 variants)
• Normal pregnancy (1 variants)
• Intellectual disability (1 variants)
• Neurodevelopmental abnormality (1 variants)
• TCF7L2-related Intellectual disability (1 variants)
• Neurodevelopmental delay (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TCF7L2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				12	2	14
missense			29	5	4	38
nonsense	3		1			4
start loss						0
frameshift	1	2				3
inframe indel						0
splice donor/acceptor (+/-2bp)	1					1
splice region			1	2		3
non coding			1	1	44	46
Total	5	2	31	18	50

Variants in TCF7L2

This is a list of pathogenic ClinVar variants found in the TCF7L2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
10-112950260-G-T			Benign (Jun 15, 2019)
10-112950403-TC-T			Benign (Aug 15, 2019)
10-112950449-G-GT			Benign (Aug 19, 2019)
10-112950801-C-T			Benign (Dec 31, 2019)
10-112950838-G-C			Uncertain significance (Jun 01, 2023)
10-112950840-G-A			Likely benign (Apr 03, 2018)
10-112950840-G-C			Uncertain significance (-)
10-112950906-T-A		Inborn genetic diseases	Uncertain significance (Jun 21, 2023)
10-112951110-AC-A			Benign (Apr 01, 2020)
10-112951217-G-A			Uncertain significance (Jun 01, 2023)
10-112951236-A-G			Likely benign (May 17, 2018)
10-112951514-G-T		Intellectual disability	Uncertain significance (Dec 21, 2023)
10-112951522-C-A		TCF7L2-related condition	Uncertain significance (Dec 06, 2023)
10-112951574-C-T			Benign (Mar 01, 2024)
10-112951617-T-C			Likely benign (Feb 25, 2018)
10-112951635-C-A			Benign (Aug 16, 2019)
10-112951893-A-AG			Benign (Aug 15, 2019)
10-112951913-C-CT			Benign (Jun 14, 2019)
10-112951918-C-T			Benign (Jun 14, 2019)
10-112964571-G-A		Intellectual disability • Inborn genetic diseases	Uncertain significance (Dec 28, 2023)
10-112964583-T-C		Inborn genetic diseases	Uncertain significance (Aug 02, 2022)
10-112964590-C-T		Inborn genetic diseases	Uncertain significance (Mar 07, 2024)
10-112964711-GATA-G			Benign (Aug 16, 2019)
10-112964714-A-G			Benign (Aug 15, 2019)
10-112964739-A-G			Benign (Aug 16, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TCF7L2	protein_coding	protein_coding	ENST00000543371	14	217429

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.995	0.00463	125725	0	23	125748	0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.40	227	354	0.641	0.0000209	3834
Missense in Polyphen		97	220.13	0.44065		2350
Synonymous	-2.11	203	168	1.21	0.0000119	1223
Loss of Function	4.73	4	33.5	0.119	0.00000179	368

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000211	0.000211
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000116	0.000114
Middle Eastern	0.000109	0.000109
South Asian	0.0000661	0.0000653
Other	0.000166	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner. Acts as repressor in the absence of CTNNB1, and as activator in its presence. Activates transcription from promoters with several copies of the Tcf motif 5'-CCTTTGATC-3' in the presence of CTNNB1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7L2/TCF4 and CTNNB1. Expression of dominant-negative mutants results in cell-cycle arrest in G1. Necessary for the maintenance of the epithelial stem-cell compartment of the small intestine. {ECO:0000269|PubMed:12408868, ECO:0000269|PubMed:12727872, ECO:0000269|PubMed:19443654, ECO:0000269|PubMed:22699938, ECO:0000269|PubMed:9727977}.
• Disease: DISEASE: Note=Constitutive activation and subsequent transactivation of target genes may lead to the maintenance of stem-cell characteristics (cycling and longevity) in cells that should normally undergo terminal differentiation and constitute the primary transforming event in colorectal cancer (CRC).; DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:16415884, ECO:0000269|PubMed:24390345}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Gastric cancer - Homo sapiens (human);Adherens junction - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Acute myeloid leukemia - Homo sapiens (human);Breast cancer - Homo sapiens (human);Basal cell carcinoma - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);Thyroid cancer - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Arrhythmogenic Right Ventricular Cardiomyopathy;Wnt Signaling Pathway;Amplification and Expansion of Oncogenic Pathways as Metastatic Traits;Wnt Signaling Pathway and Pluripotency;Endometrial cancer;Chromosomal and microsatellite instability in colorectal cancer;Wnt Signaling Pathway;DNA Damage Response (only ATM dependent);Degradation of beta-catenin by the destruction complex;Signaling by WNT;Signal Transduction;Gene expression (Transcription);RUNX3 regulates WNT signaling;Transcriptional regulation by RUNX3;Generic Transcription Pathway;Repression of WNT target genes;RNA Polymerase II Transcription;Deactivation of the beta-catenin transactivating complex;Ca2+ pathway;Beta-catenin independent WNT signaling;Wnt;ID;Wnt Canonical;Regulation of nuclear beta catenin signaling and target gene transcription;AP-1 transcription factor network;Binding of TCF/LEF:CTNNB1 to target gene promoters;Formation of the beta-catenin:TCF transactivating complex;TCF dependent signaling in response to WNT;Wnt Mammals (Consensus)

Recessive Scores

• pRec: 0.485

Intolerance Scores

• loftool: 0.0268
• rvis_EVS: -0.22
• rvis_percentile_EVS: 37.54

Haploinsufficiency Scores

• pHI: 0.490
• hipred: Y
• hipred_score: 0.825
• ghis: 0.508

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tcf7l2
• Phenotype: adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; muscle phenotype; neoplasm; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; embryo phenotype; skeleton phenotype; renal/urinary system phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: tcf7l2
• Affected structure: pancreatic B cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;blood vessel development;regulation of transcription, DNA-templated;regulation of transcription by RNA polymerase II;cell cycle arrest;Wnt signaling pathway, calcium modulating pathway;cell population proliferation;response to glucose;positive regulation of heparan sulfate proteoglycan biosynthetic process;pancreas development;positive regulation of insulin secretion;positive regulation of protein binding;regulation of hormone metabolic process;glucose homeostasis;negative regulation of DNA-binding transcription factor activity;maintenance of DNA repeat elements;canonical Wnt signaling pathway involved in positive regulation of epithelial to mesenchymal transition;fat cell differentiation;negative regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of protein export from nucleus;myoblast fate commitment;regulation of smooth muscle cell proliferation;positive regulation of protein kinase B signaling;canonical Wnt signaling pathway;negative regulation of canonical Wnt signaling pathway;beta-catenin-TCF complex assembly;negative regulation of type B pancreatic cell apoptotic process;negative regulation of extrinsic apoptotic signaling pathway
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;transcription factor complex;PML body;protein-DNA complex;beta-catenin-TCF7L2 complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;RNA polymerase II repressing transcription factor binding;chromatin binding;DNA-binding transcription factor activity;protein binding;beta-catenin binding;transcription factor binding;protein kinase binding;nuclear hormone receptor binding;sequence-specific DNA binding;transcription regulatory region DNA binding;gamma-catenin binding;armadillo repeat domain binding