MSX2

msh homeobox 2, the group of NKL subclass homeoboxes and pseudogenes

Basic information

Region (hg38): 5:174724582-174730896

Previous symbols: [ "PFM1" ]

Links

ENSG00000120149 ∙ NCBI:4488 ∙ OMIM:123101 ∙ HGNC:7392 ∙ Uniprot:P35548 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• parietal foramina with cleidocranial dysplasia (Definitive), mode of inheritance: AD
• craniosynostosis 2 (Definitive), mode of inheritance: AD
• craniosynostosis 2 (Strong), mode of inheritance: AD
• craniosynostosis 2 (Supportive), mode of inheritance: AD
• parietal foramina (Supportive), mode of inheritance: AD
• parietal foramina with cleidocranial dysplasia (Supportive), mode of inheritance: AD
• parietal foramina with cleidocranial dysplasia (Limited), mode of inheritance: AD
• craniosynostosis 2 (Moderate), mode of inheritance: AD
• parietal foramina 1 (Moderate), mode of inheritance: AD
• craniosynostosis 2 (Strong), mode of inheritance: AD
• parietal foramina 1 (Strong), mode of inheritance: AD
• parietal foramina (Definitive), mode of inheritance: AD
• craniosynostosis 2 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Craniosynostosis 2; Parietal foramina with cleidocranial dysplasia; Parietal foramina 1	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; Musculoskeletal	8106171; 8357019; 10742103; 14571277; 16222674; 16319823; 16642368; 17955513; 18000908; 19533795; 21082653
Upstream microduplications have been described as causing Cleidocranial dysplasia

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MSX2 gene.

• Cranium bifidum occultum (4 variants)
• Craniosynostosis 2 (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MSX2 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	22	5	28
missense	2		68	6	1	77
nonsense	1	1				2
start loss		1	1			2
frameshift	1		1			2
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region			1	2		3
non coding			26	20	31	77
Total	4	2	99	48	37

Variants in MSX2

This is a list of pathogenic ClinVar variants found in the MSX2 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-174724604-C-A		Parietal foramina 1 • Craniosynostosis 2	Benign (Mar 06, 2018)
5-174724610-C-T		Craniosynostosis 2 • Parietal foramina 1	Uncertain significance (Jan 13, 2018)
5-174724618-C-T		Craniosynostosis 2 • Parietal foramina 1	Benign/Likely benign (Jan 13, 2018)
5-174724643-C-G		Parietal foramina 1 • Craniosynostosis 2	Benign (Dec 24, 2018)
5-174724660-A-G			Likely pathogenic (Aug 04, 2024)
5-174724661-T-C		Cranium bifidum occultum	Uncertain significance (May 26, 2023)
5-174724681-A-C		Cranium bifidum occultum	Likely benign (Jul 06, 2022)
5-174724682-A-G		Cranium bifidum occultum • MSX2-related disorder	Likely benign (Dec 24, 2022)
5-174724698-C-T		Cranium bifidum occultum	Likely benign (Jun 11, 2022)
5-174724702-G-A		Cranium bifidum occultum	Uncertain significance (Jul 27, 2022)
5-174724703-A-G		Craniosynostosis 2	Uncertain significance (Jul 17, 2023)
5-174724708-G-A		Cranium bifidum occultum • MSX2-related disorder	Benign (Jun 05, 2023)
5-174724709-G-T		Cranium bifidum occultum	Uncertain significance (May 25, 2022)
5-174724732-G-C		Inborn genetic diseases • Cranium bifidum occultum	Uncertain significance (Jun 10, 2023)
5-174724736-C-T		Cranium bifidum occultum	Uncertain significance (Sep 15, 2021)
5-174724740-G-A		not specified	Likely benign (Apr 26, 2024)
5-174724742-C-T		Cranium bifidum occultum	Uncertain significance (Feb 10, 2022)
5-174724754-A-T		Cranium bifidum occultum • Inborn genetic diseases	Uncertain significance (Nov 24, 2023)
5-174724762-G-C		MSX2-related disorder	Uncertain significance (Jul 08, 2020)
5-174724775-G-T		Cranium bifidum occultum • Inborn genetic diseases	Uncertain significance (Jul 06, 2023)
5-174724776-C-T		Cranium bifidum occultum	Benign (Dec 02, 2023)
5-174724781-A-T		Parietal foramina 1 • Craniosynostosis 2	Uncertain significance (Jan 13, 2018)
5-174724786-T-C		Cranium bifidum occultum	Uncertain significance (Mar 18, 2023)
5-174724802-G-C		Cranium bifidum occultum	Uncertain significance (Aug 21, 2021)
5-174724811-C-T		Cranium bifidum occultum	Uncertain significance (May 03, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MSX2	protein_coding	protein_coding	ENST00000239243	2	6361

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.262	0.715	125733	0	1	125734	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.471	141	158	0.894	0.00000816	1669
Missense in Polyphen		41	52.295	0.78401		582
Synonymous	0.181	70	72.0	0.973	0.00000388	582
Loss of Function	1.90	2	7.68	0.260	3.84e-7	88

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000879	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as a transcriptional regulator in bone development. Represses the ALPL promoter activity and antagonizes the stimulatory effect of DLX5 on ALPL expression during osteoblast differentiation. Probable morphogenetic role. May play a role in limb-pattern formation. In osteoblasts, suppresses transcription driven by the osteocalcin FGF response element (OCFRE). Binds to the homeodomain-response element of the ALPL promoter. {ECO:0000269|PubMed:12145306}.
• Disease: DISEASE: Parietal foramina 1 (PFM1) [MIM:168500]: Autosomal dominant disease characterized by oval defects of the parietal bones caused by deficient ossification around the parietal notch, which is normally obliterated during the fifth fetal month. {ECO:0000269|PubMed:10742103, ECO:0000269|PubMed:10767351}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Parietal foramina with cleidocranial dysplasia (PFMCCD) [MIM:168550]: Combines skull defects in the form of enlarged parietal foramina and deficient ossification of the clavicles. {ECO:0000269|PubMed:14571277}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Craniosynostosis 2 (CRS2) [MIM:604757]: A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. CRS2 is characterized by either fronto-orbital recession, or frontal bossing, or turribrachycephaly, or cloverleaf skull. Associated features include severe headache, high incidence of visual problems (myopia or hyperopia), and short first metatarsals. Intelligence is normal. {ECO:0000269|PubMed:23918290, ECO:0000269|PubMed:23949913, ECO:0000269|PubMed:8106171}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: HTLV-I infection - Homo sapiens (human);Neural Crest Differentiation;Hair Follicle Development- Induction (Part 1 of 3);Transcriptional regulation by RUNX2;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;Regulation of RUNX2 expression and activity (Consensus)

Recessive Scores

• pRec: 0.342

Haploinsufficiency Scores

• pHI: 0.820
• hipred: Y
• hipred_score: 0.862
• ghis: 0.459

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.426

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Msx2
• Phenotype: immune system phenotype; skeleton phenotype; hearing/vestibular/ear 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); limbs/digits/tail phenotype; digestive/alimentary phenotype; vision/eye 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); normal phenotype; 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; pigmentation phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); muscle phenotype; craniofacial 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; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;osteoblast differentiation;chondrocyte development;osteoblast development;outflow tract septum morphogenesis;epithelial to mesenchymal transition involved in endocardial cushion formation;endochondral bone growth;negative regulation of cell population proliferation;anterior/posterior pattern specification;signal transduction involved in regulation of gene expression;positive regulation of BMP signaling pathway;negative regulation of CREB transcription factor activity;embryonic forelimb morphogenesis;embryonic hindlimb morphogenesis;wound healing, spreading of epidermal cells;embryonic nail plate morphogenesis;negative regulation of apoptotic process;negative regulation of fat cell differentiation;negative regulation of keratinocyte differentiation;positive regulation of osteoblast differentiation;negative regulation of transcription, DNA-templated;embryonic morphogenesis;stem cell differentiation;positive regulation of timing of catagen;bone trabecula formation;cranial suture morphogenesis;frontal suture morphogenesis;branching involved in mammary gland duct morphogenesis;BMP signaling pathway involved in heart development;enamel mineralization;cellular response to estradiol stimulus;activation of meiosis;negative regulation of transcription regulatory region DNA binding;positive regulation of mesenchymal cell apoptotic process
• Cellular component: nucleus;cytosol;nuclear speck
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription repressor activity, RNA polymerase II-specific;transcription coregulator activity;protein binding;transcription factor binding;sequence-specific DNA binding;transcription regulatory region DNA binding