RUNX2

RUNX family transcription factor 2, the group of Runt-related transcription factors

Basic information

Region (hg38): 6:45328156-45664349

Previous symbols: [ "CCD", "CBFA1", "CCD1" ]

Links

ENSG00000124813 ∙ NCBI:860 ∙ OMIM:600211 ∙ HGNC:10472 ∙ Uniprot:Q13950 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cleidocranial dysplasia 1 (Definitive), mode of inheritance: AD
• metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (Moderate), mode of inheritance: AD
• cleidocranial dysplasia 1 (Definitive), mode of inheritance: AD
• cleidocranial dysplasia 1 (Supportive), mode of inheritance: AD
• metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (Supportive), mode of inheritance: AD
• cleidocranial dysplasia 1 (Strong), mode of inheritance: AD
• metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cleidocranial dysplasia 1; Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Dental; Musculoskeletal	14818746; 2301472; 9182765; 10545612; 11746020; 12424590; 16222673; 15952089; 20301686; 20683987; 21734816; 22023169; 22194205; 23220435; 23290074; 23348268; 23558979; 23659235
Duplications including the gene have also been reported as resulting in additional skeletal anomalies such as craniosynostosis

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RUNX2 gene.

• not provided (66 variants)
• Cleidocranial dysostosis (20 variants)
• Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome;Cleidocranial dysostosis (2 variants)
• RUNX2-related disorder (2 variants)
• not specified (1 variants)
• Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RUNX2 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	1	1	2	56	5	65
missense	16	10	105	4		135
nonsense	24	1	1			26
start loss	1					1
frameshift	37	5	2			44
inframe indel			39	4		43
splice donor/acceptor (+/-2bp)	4	9				13
splice region			8	4	1	13
non coding			50	31	45	126
Total	83	26	199	95	50

Highest pathogenic variant AF is 0.00000659

Variants in RUNX2

This is a list of pathogenic ClinVar variants found in the RUNX2 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-45328407-T-C		Cleidocranial dysostosis	Benign (Jan 13, 2018)
6-45328602-A-G			Likely benign (Mar 10, 2019)
6-45328647-G-T		Cleidocranial dysostosis	Benign (Jan 13, 2018)
6-45328661-T-C			Likely benign (Apr 16, 2020)
6-45328663-T-C		Cleidocranial dysostosis	Benign (Jan 13, 2018)
6-45328687-C-T		Cleidocranial dysostosis	Uncertain significance (Jan 12, 2018)
6-45328715-AAAG-A		Cleidocranial dysostosis	Benign/Likely benign (Feb 01, 2024)
6-45328729-G-A			Pathogenic (Jan 01, 2019)
6-45328740-G-C			Uncertain significance (Oct 15, 2022)
6-45328754-G-GT		Cleidocranial dysostosis	Pathogenic (May 23, 2020)
6-45328760-C-T			Uncertain significance (Nov 16, 2023)
6-45328769-C-A		Inborn genetic diseases	Uncertain significance (Aug 14, 2023)
6-45328780-T-C		Cleidocranial dysostosis	Uncertain significance (Jan 13, 2018)
6-45328791-G-A			Likely benign (Sep 27, 2023)
6-45328793-T-C			Likely benign (Feb 08, 2023)
6-45328802-T-A			Likely benign (Mar 18, 2023)
6-45328881-T-C			Benign (Aug 09, 2018)
6-45371886-CA-C			Uncertain significance (Nov 03, 2021)
6-45421552-T-C			Benign (Jan 22, 2024)
6-45421921-T-A			Benign (Nov 13, 2019)
6-45422104-G-A			Likely benign (Aug 30, 2018)
6-45422351-G-T			Likely benign (Oct 21, 2018)
6-45422583-A-T			Likely benign (Sep 04, 2022)
6-45422587-C-T			Uncertain significance (Feb 05, 2022)
6-45422591-A-G			Likely pathogenic (Aug 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RUNX2	protein_coding	protein_coding	ENST00000371438	8	336193

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.949	0.0512	117830	0	2	117832	0.00000849

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.60	225	304	0.741	0.0000175	3392
Missense in Polyphen		105	155.33	0.67598		1681
Synonymous	-1.88	150	123	1.21	0.00000753	1078
Loss of Function	3.82	3	22.6	0.133	0.00000119	230

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000614	0.0000588
Finnish	0.00	0.00
European (Non-Finnish)	0.0000190	0.00000936
Middle Eastern	0.0000614	0.0000588
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor involved in osteoblastic differentiation and skeletal morphogenesis (PubMed:28505335, PubMed:28738062, PubMed:28703881). Essential for the maturation of osteoblasts and both intramembranous and endochondral ossification. CBF binds to the core site, 5'-PYGPYGGT-3', of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, osteocalcin, osteopontin, bone sialoprotein, alpha 1(I) collagen, LCK, IL-3 and GM-CSF promoters. In osteoblasts, supports transcription activation: synergizes with SPEN/MINT to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE) (By similarity). Inhibits KAT6B-dependent transcriptional activation. {ECO:0000250, ECO:0000269|PubMed:11965546, ECO:0000269|PubMed:28505335, ECO:0000269|PubMed:28703881, ECO:0000269|PubMed:28738062}.
• Disease: DISEASE: Cleidocranial dysplasia (CLCD) [MIM:119600]: Autosomal dominant skeletal disorder with high penetrance and variable expressivity. It is due to defective endochondral and intramembranous bone formation. Typical features include hypoplasia/aplasia of clavicles, patent fontanelles, wormian bones (additional cranial plates caused by abnormal ossification of the calvaria), supernumerary teeth, short stature, and other skeletal changes. In some cases defects in RUNX2 are exclusively associated with dental anomalies. {ECO:0000269|PubMed:10521292, ECO:0000269|PubMed:10545612, ECO:0000269|PubMed:10689183, ECO:0000269|PubMed:10980549, ECO:0000269|PubMed:11857736, ECO:0000269|PubMed:12081718, ECO:0000269|PubMed:12196916, ECO:0000269|PubMed:12424590, ECO:0000269|PubMed:16270353, ECO:0000269|PubMed:19744171, ECO:0000269|PubMed:20082269, ECO:0000269|PubMed:20648631, ECO:0000269|PubMed:24984680, ECO:0000269|PubMed:28505335, ECO:0000269|PubMed:28703881, ECO:0000269|PubMed:28738062, ECO:0000269|PubMed:9182765, ECO:0000269|PubMed:9207800}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) [MIM:156510]: An autosomal dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth. {ECO:0000269|PubMed:23290074}. Note=The disease is caused by mutations affecting the gene represented in this entry. Analysis for copy-number variations revealed that a 105 kb duplication within RUNX2 segregated with the MDMHB phenotype in a region with maximum linkage. Real-time PCR for copy-number variation in genomic DNA in eight samples, as well as sequence analysis of fibroblast cDNA from one subject with MDMHB confirmed that affected family members were heterozygous for the presence of an intragenic duplication encompassing exons 3 to 5 of RUNX2. These three exons code for the Q/A domain and the functionally essential DNA-binding Runt domain of RUNX2. The RUNX2 duplication found in individuals with MDMHB leads to a gain of function (PubMed:23290074). {ECO:0000269|PubMed:23290074}.
• Pathway: Transcriptional misregulation in cancer - Homo sapiens (human);Androgen receptor signaling pathway;Bone Morphogenic Protein (BMP) Signalling and Regulation;Cell Differentiation - Index expanded;Interleukin-11 Signaling Pathway;TGF-beta Signaling Pathway;Hypothesized Pathways in Pathogenesis of Cardiovascular Disease;TGF-B Signaling in Thyroid Cells for Epithelial-Mesenchymal Transition;Development of pulmonary dendritic cells and macrophage subsets;Role of Osx and miRNAs in tooth development;Endochondral Ossification;TGF-beta Receptor Signaling;RUNX2 regulates osteoblast differentiation;RUNX2 regulates chondrocyte maturation;RUNX2 regulates bone development;RUNX2 regulates genes involved in cell migration;RUNX2 regulates genes involved in differentiation of myeloid cells;Transcriptional regulation by RUNX2;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;YAP1- and WWTR1 (TAZ)-stimulated gene expression;AndrogenReceptor;TGF_beta_Receptor;Leptin;Notch-mediated HES/HEY network;Regulation of retinoblastoma protein;Regulation of nuclear SMAD2/3 signaling;FGF signaling pathway;Regulation of RUNX2 expression and activity (Consensus)

Recessive Scores

• pRec: 0.876

Intolerance Scores

• loftool: 0.0449
• rvis_EVS: -0.45
• rvis_percentile_EVS: 24.33

Haploinsufficiency Scores

• pHI: 0.533
• hipred: Y
• hipred_score: 0.782
• ghis: 0.557

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.722

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Runx2
• Phenotype: craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; reproductive system phenotype; 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); 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); 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); hematopoietic system phenotype; growth/size/body region phenotype; vision/eye phenotype; limbs/digits/tail phenotype; digestive/alimentary phenotype; skeleton phenotype; immune system phenotype; respiratory system phenotype; liver/biliary system phenotype

Zebrafish Information Network

• Gene name: runx2b
• Affected structure: trunk
• Phenotype tag: abnormal
• Phenotype quality: decreased length

Gene ontology

• Biological process: ossification;osteoblast differentiation;endochondral ossification;osteoblast fate commitment;chondrocyte development;osteoblast development;transcription initiation from RNA polymerase II promoter;positive regulation of cell population proliferation;hemopoiesis;neuron differentiation;T cell differentiation;BMP signaling pathway;positive regulation of chondrocyte differentiation;embryonic forelimb morphogenesis;regulation of fibroblast growth factor receptor signaling pathway;odontogenesis of dentin-containing tooth;regulation of odontogenesis of dentin-containing tooth;positive regulation of osteoblast differentiation;negative regulation of smoothened signaling pathway;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;cell maturation;embryonic cranial skeleton morphogenesis;stem cell differentiation;cellular response to BMP stimulus;positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;transcription factor complex;cytosol
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;chromatin binding;DNA-binding transcription factor activity;protein binding;ATP binding;protein domain specific binding;bHLH transcription factor binding;repressing transcription factor binding