CCM2

CCM2 scaffold protein, the group of CCM adhesion complex

Basic information

Region (hg38): 7:44999475-45076469

Previous symbols: [ "C7orf22" ]

Links

ENSG00000136280 ∙ NCBI:83605 ∙ OMIM:607929 ∙ HGNC:21708 ∙ Uniprot:Q9BSQ5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cerebral cavernous malformation 2 (Strong), mode of inheritance: AD
• cerebral cavernous malformation 2 (Strong), mode of inheritance: AD
• famililal cerebral cavernous malformations (Supportive), mode of inheritance: AD
• cerebral cavernous malformation 2 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cerebral cavernous malformations 2	AD	Cardiovascular; Neurologic; Pharmacogenomic	Surveillance measures (eg, spinal cord MRI, annual brain gradient echo or susceptibility-weighted imaging) has been advocated; Agents that increase risk of hemorrhage should be avoided (eg, aspirin, NSAIDs, heparin, warfarin).	Cardiovascular; Neurologic	14624391; 17211633; 17160895; 18060436; 18779516; 19088123; 21543988; 20301470

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CCM2 gene.

• Cerebral_cavernous_malformation_2 (210 variants)
• not_provided (96 variants)
• Inborn_genetic_diseases (88 variants)
• CCM2-related_disorder (20 variants)
• not_specified (18 variants)
• Cerebral_cavernous_malformation (4 variants)
• Vascular_dementia (2 variants)
• Vasculitis (1 variants)
• Cavernous_hemangioma (1 variants)
• Subcutaneous_venous_lacunae (1 variants)
• Cerebral_cavernous_angioma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CCM2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000031443.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		2		59	3	64
missense	6	3	104	16	2	131
nonsense	17	5				22
start loss	1		1			2
frameshift	39	13	1			53
splice donor/acceptor (+/-2bp)	12	9				21
Total	75	32	106	75	5

Highest pathogenic variant AF is 0.000025369

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CCM2	protein_coding	protein_coding	ENST00000381112	10	76995

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00928	0.989	125737	0	11	125748	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.518	244	268	0.911	0.0000177	3042
Missense in Polyphen		74	107.67	0.68728		1166
Synonymous	-0.957	130	117	1.11	0.00000863	924
Loss of Function	2.68	7	19.9	0.351	9.70e-7	243

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)	0.0000444	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.000163	0.000163
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions (By similarity). May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3- dependent p38 activation induced by hyperosmotic shock (By similarity). {ECO:0000250}.
• Disease: DISEASE: Cerebral cavernous malformations 2 (CCM2) [MIM:603284]: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. {ECO:0000269|PubMed:14624391, ECO:0000269|PubMed:14740320, ECO:0000269|PubMed:22415356}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Regulation of p38-alpha and p38-beta;p38 MAPK signaling pathway (Consensus)

Recessive Scores

• pRec: 0.116

Intolerance Scores

• loftool: 0.292
• rvis_EVS: -0.38
• rvis_percentile_EVS: 28.11

Haploinsufficiency Scores

• pHI: 0.180
• hipred: Y
• hipred_score: 0.580
• ghis: 0.527

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.700

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ccm2
• Phenotype: embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); normal 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); 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; 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); vision/eye phenotype; immune system 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; muscle phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: ccm2
• Affected structure: blood vessel endothelial cell
• Phenotype tag: abnormal
• Phenotype quality: decreased length

Gene ontology

• Biological process: vasculogenesis;in utero embryonic development;endothelial cell development;integrin-mediated signaling pathway;multicellular organism growth;cell-cell junction organization;inner ear development;venous blood vessel morphogenesis;stress-activated MAPK cascade;pericardium development;blood vessel endothelial cell differentiation;endothelial tube morphogenesis
• Cellular component: cytoplasm;mitochondrion;protein-containing complex
• Molecular function: protein binding