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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

ENSG00000124813NCBI:860OMIM:600211HGNC:10472Uniprot:Q13950AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

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

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Cleidocranial dysplasia 1; Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactylyADGeneralGenetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testingCraniofacial; Dental; Musculoskeletal14818746; 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 (299 variants)
  • Cleidocranial dysostosis (137 variants)
  • not specified (12 variants)
  • Inborn genetic diseases (9 variants)
  • Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (4 variants)
  • RUNX2-related condition (4 variants)
  • Cleidocranial dysostosis;Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (3 variants)
  • Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome;Cleidocranial dysostosis (2 variants)
  • Orofacial cleft 1 (1 variants)
  • Retinal cone dystrophy 3A (1 variants)
  • Craniosynostosis syndrome (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
clinvar
1
clinvar
2
clinvar
42
clinvar
4
clinvar
50
missense
15
clinvar
10
clinvar
85
clinvar
4
clinvar
114
nonsense
22
clinvar
1
clinvar
1
clinvar
24
start loss
1
clinvar
1
frameshift
35
clinvar
5
clinvar
2
clinvar
42
inframe indel
32
clinvar
2
clinvar
34
splice donor/acceptor (+/-2bp)
4
clinvar
7
clinvar
11
splice region
?
0
non coding
?
50
clinvar
25
clinvar
44
clinvar
119
Total 78 24 172 73 48

Highest pathogenic variant AF is 0.00000661

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)357085
6-45328602-A-G Likely benign (Mar 10, 2019)1196317
6-45328647-G-T Cleidocranial dysostosis Benign (Jan 13, 2018)357086
6-45328661-T-C Likely benign (Apr 16, 2020)1207597
6-45328663-T-C Cleidocranial dysostosis Benign (Jan 13, 2018)357087
6-45328687-C-T Cleidocranial dysostosis Uncertain significance (Jan 12, 2018)357088
6-45328715-AAAG-A Cleidocranial dysostosis Benign/Likely benign (Aug 01, 2022)357089
6-45328729-G-A Pathogenic (Jan 01, 2019)634442
6-45328740-G-C Uncertain significance (Oct 15, 2022)1942097
6-45328754-G-GT Cleidocranial dysostosis Pathogenic (May 23, 2020)916707
6-45328769-C-A Inborn genetic diseases Uncertain significance (Aug 14, 2023)2598989
6-45328780-T-C Cleidocranial dysostosis Uncertain significance (Jan 13, 2018)911151
6-45328791-G-A Likely benign (Jul 01, 2022)1161520
6-45328793-T-C Likely benign (Feb 08, 2023)1577874
6-45328881-T-C Benign (Aug 09, 2018)1277725
6-45371886-CA-C Uncertain significance (Nov 03, 2021)1319362
6-45421552-T-C Benign (Jan 22, 2024)1164339
6-45421921-T-A Benign (Nov 13, 2019)1266687
6-45422104-G-A Likely benign (Aug 30, 2018)1204787
6-45422351-G-T Likely benign (Oct 21, 2018)1196572
6-45422583-A-T Likely benign (Sep 04, 2022)1902600
6-45422587-C-T Uncertain significance (Feb 05, 2022)1463122
6-45422591-A-G Likely pathogenic (Aug 27, 2023)2729445
6-45422597-G-C Likely benign (Nov 28, 2023)2741107
6-45422608-G-A Uncertain significance (Nov 23, 2021)1377457

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
RUNX2protein_codingprotein_codingENST00000371438 8336193
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
0.9490.0512117830021178320.00000849
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense1.602253040.7410.00001753392
Missense in Polyphen105155.330.675981681
Synonymous-1.881501231.210.000007531078
Loss of Function3.82322.60.1330.00000119230

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.000.00
Ashkenazi Jewish0.000.00
East Asian0.00006140.0000588
Finnish0.000.00
European (Non-Finnish)0.00001900.00000936
Middle Eastern0.00006140.0000588
South Asian0.000.00
Other0.000.00

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

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

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