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    CCM2 CCM2 scaffold protein [ Homo sapiens (human) ]

    Gene ID: 83605, updated on 3-Apr-2024

    Summary

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    Official Symbol
    CCM2provided by HGNC
    Official Full Name
    CCM2 scaffold proteinprovided by HGNC
    Primary source
    HGNC:HGNC:21708
    See related
    Ensembl:ENSG00000136280 MIM:607929; AllianceGenome:HGNC:21708
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    OSM; C7orf22; PP10187
    Summary
    This gene encodes a scaffold protein that functions in the stress-activated p38 Mitogen-activated protein kinase (MAPK) signaling cascade. The protein interacts with SMAD specific E3 ubiquitin protein ligase 1 (also known as SMURF1) via a phosphotyrosine binding domain to promote RhoA degradation. The protein is required for normal cytoskeletal structure, cell-cell interactions, and lumen formation in endothelial cells. Mutations in this gene result in cerebral cavernous malformations. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]
    Expression
    Ubiquitous expression in lymph node (RPKM 10.3), spleen (RPKM 8.5) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    Location:
    7p13
    Exon count:
    14
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 7 NC_000007.14 (44999746..45076470)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 7 NC_060931.1 (45160321..45237028)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 7 NC_000007.13 (45039345..45116069)

    Chromosome 7 - NC_000007.14Genomic Context describing neighboring genes Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr7:45001789-45002289 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25958 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 18159 Neighboring gene myosin IG Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 18160 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25959 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25960 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25961 Neighboring gene ReSE screen-validated silencer GRCh37_chr7:45024687-45024867 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr7:45025394-45026140 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr7:45026141-45026888 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr7:45030540-45031094 Neighboring gene uncharacterized LOC102723334 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25964 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25966 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25965 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25963 Neighboring gene small nucleolar RNA host gene 15 Neighboring gene small nucleolar RNA, H/ACA box 9 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 18161 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 18162 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 18163 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25967 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25968 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr7:45112087-45112746 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr7:45112747-45113406 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_99227 Neighboring gene NAC alpha domain containing Neighboring gene ReSE screen-validated silencer GRCh37_chr7:45143162-45143329 Neighboring gene transforming growth factor beta regulator 4 Neighboring gene small nucleolar RNA, H/ACA box 5A

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene. Gallione CJ, et al. Hum Genet, 2022 Nov. PMID 35488064, Free PMC Article
    2. A British family with familial cerebral cavernous malformation due to a rare mutation of the CCM2 gene. Noushad M, et al. Acta Neurol Belg, 2020 Oct. PMID 32170606
    3. Two Novel CCM2 Heterozygous Mutations Associated with Cerebral Cavernous Malformation in a Chinese Family. Du Q, et al. J Mol Neurosci, 2019 Mar. PMID 30701383
    4. First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing. Spiegler S, et al. Neurogenetics, 2018 Jan. PMID 29197946
    5. A Novel MGC4607/CCM2 Gene Mutation Associated with Cerebral Spinal and Cutaneous Cavernous Angiomas. Cigoli MS, et al. J Mol Neurosci, 2015 Jul. PMID 25869611

    See all (83) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene.
      Title: Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene.
    2. Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.
      Title: Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.
    3. A British family with familial cerebral cavernous malformation due to a rare mutation of the CCM2 gene.
      Title: A British family with familial cerebral cavernous malformation due to a rare mutation of the CCM2 gene.
    4. CCM1 and CCM2 variants in patients with cerebral cavernous malformation in an ethnically Chinese population in Taiwan.
      Title: CCM1 and CCM2 variants in patients with cerebral cavernous malformation in an ethnically Chinese population in Taiwan.
    5. Emerging roles of CCM genes during tumorigenesis with potential application as novel biomarkers across major types of cancers.
      Title: Emerging roles of CCM genes during tumorigenesis with potential application as novel biomarkers across major types of cancers.
    6. showed a population-specific mutational and clinical spectrum of multiple CCMs. These findings broaden the mutational spectrum in CCMs and highlight the importance of screening for deletions in the CCM genes in patients with multiple CCMs
      Title: Mutational analysis of CCM1, CCM2 and CCM3 in a Han Chinese cohort with multiple cerebral cavernous malformations in Taiwan.
    7. Sanger sequencing of CCM2 in patients with cerebral cavernous malformation (CCM) identified many mutations, some of which are germline mutations in a cohort of Italian patients.
      Title: A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion.
    8. Study revealed a heterozygous 24 kB inversion including exon 1 of CCM2 in a 12-year-old boy with familial cerebral cavernous malformation.
      Title: First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing.
    9. Two novel heterozygous mutations in the CCM2 gene were identified as a cause of cerebral cavernous malformation in a Chinese family.
      Title: Two Novel CCM2 Heterozygous Mutations Associated with Cerebral Cavernous Malformation in a Chinese Family.
    10. Case-control study to investigate the possible association of others polymorphisms (c.485+65 C/G, c.989+63 C/G, c.1980 A/G in CCM1 gene, c.472+127 C/T in CCM2 and c.150 G/A in CCM3) with cerebral cavernous malformations. The five polymorphisms were characterized in 64 sporadic patients and in 90 healthy controls by ASO-PCR. Results suggest that some polymorphisms in CCM genes could play an important role in the disease.
      Title: Relevance of CCM gene polymorphisms for clinical management of sporadic cerebral cavernous malformations.
    Submit: New GeneRIF Correction See all GeneRIFs (52)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Cerebral cavernous malformation 2
    MedGen: C1864041 OMIM: 603284 GeneReviews: Familial Cerebral Cavernous Malformation
    		Compare labs

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • MGC4067, MGC4607, MGC74868

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in blood vessel endothelial cell differentiation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in cell-cell junction organization IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in endothelial cell development IEA
    Inferred from Electronic Annotation
    more info
    		  
    acts_upstream_of_or_within endothelial tube morphogenesis IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in endothelium development NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    involved_in heart development IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in in utero embryonic development IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in inner ear development IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in integrin-mediated signaling pathway TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in multicellular organism growth IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in pericardium development IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in regulation of angiogenesis NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    involved_in stress-activated MAPK cascade TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in vasculogenesis IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in vasculogenesis IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in venous blood vessel morphogenesis IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    located_in cytoplasm IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in mitochondrion IDA
    Inferred from Direct Assay
    more info
    		  
    part_of protein-containing complex IEA
    Inferred from Electronic Annotation
    more info
    		  

    General protein information

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    Preferred Names
    cerebral cavernous malformations 2 protein
    Names
    CCM2 scaffolding protein
    cerebral cavernous malformation 2
    malcavernin
    osmosensing scaffold for MEKK3

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_016295.1 RefSeqGene

      Range
      4559..81283
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_664

    mRNA and Protein(s)

    1. NM_001029835.2 → NP_001025006.1  cerebral cavernous malformations 2 protein isoform 1

      See identical proteins and their annotated locations for NP_001025006.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).
      Source sequence(s)
      AI538498, AK098005, BC004903
      Consensus CDS
      CCDS34630.1
      UniProtKB/TrEMBL
      A0A0A0MT72
      Related
      ENSP00000370503.3, ENST00000381112.7
      Conserved Domains (2) summary
      cd13166
      Location:64 → 258
      PTB_CCM2; Cerebral cavernous malformation 2 FERM domain C-lobe
      pfam16545
      Location:308 → 398
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology

    2. NM_001167934.2 → NP_001161406.1  cerebral cavernous malformations 2 protein isoform 3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) represents use of an alternate promoter and 5' UTR, uses a distinct start codon, and lacks an alternate in-frame exon, compared to variant 1. The resulting isoform (3) has a shorter and distinct N-terminus, compared to isoform 1.
      Source sequence(s)
      AC004847, AC013416, AI538498
      Consensus CDS
      CCDS55109.1
      UniProtKB/TrEMBL
      A0A0A0MT72
      Related
      ENSP00000444725.1, ENST00000541586.5
      Conserved Domains (2) summary
      cd13166
      Location:10 → 179
      PTB_CCM2; Cerebral cavernous malformation 2 FERM domain C-lobe
      pfam16545
      Location:229 → 319
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology

    3. NM_001167935.2 → NP_001161407.1  cerebral cavernous malformations 2 protein isoform 4

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) represents use of an alternate promoter and 5' UTR, uses a distinct start codon, and lacks two alternate in-frame exons in the central coding region, compared to variant 1. The resulting isoform (4) has a shorter and distinct N-terminus and lacks an internal segment, compared to isoform 1.
      Source sequence(s)
      AC004847, AC013416, AF370392, AI538498
      Consensus CDS
      CCDS55108.1
      UniProtKB/TrEMBL
      C9JUH3
      Related
      ENSP00000438035.1, ENST00000544363.5
      Conserved Domains (2) summary
      pfam16545
      Location:196 → 286
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology
      cl17171
      Location:43 → 191
      PH-like; Pleckstrin homology-like domain

    4. NM_001363458.2 → NP_001350387.1  cerebral cavernous malformations 2 protein isoform 5

      Status: REVIEWED

      Source sequence(s)
      AC013416, AF370392, AK098005, BC004903, BI916251, HY347636
      UniProtKB/TrEMBL
      A0A0A0MT72
      Conserved Domains (2) summary
      cd13166
      Location:43 → 237
      PTB_CCM2; Cerebral cavernous malformation 2 FERM domain C-lobe
      pfam16545
      Location:328 → 418
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology

    5. NM_001363459.2 → NP_001350388.1  cerebral cavernous malformations 2 protein isoform 6

      Status: REVIEWED

      Source sequence(s)
      AC013416, AF370392, AK098005, BC004903, CV571060, HY347636
      UniProtKB/TrEMBL
      A0A0A0MT72
      Conserved Domains (2) summary
      cd13166
      Location:10 → 179
      PTB_CCM2; Cerebral cavernous malformation 2 FERM domain C-lobe
      pfam16545
      Location:270 → 360
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology

    6. NM_031443.4 → NP_113631.1  cerebral cavernous malformations 2 protein isoform 2

      See identical proteins and their annotated locations for NP_113631.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) represents use of an alternate promoter and 5' UTR and uses a distinct start codon, compared to variant 1. The resulting isoform (2) has a shorter and distinct N-terminus, compared to isoform 1.
      Source sequence(s)
      AF370392, BC004903
      Consensus CDS
      CCDS5500.1
      UniProtKB/Swiss-Prot
      A4D2L4, B3KUV0, D3DVL4, E9PDJ3, F5H0E1, F5H551, Q71RE5, Q8TAT4, Q9BSQ5
      UniProtKB/TrEMBL
      A0A0A0MT72
      Related
      ENSP00000258781.7, ENST00000258781.11
      Conserved Domains (2) summary
      cd13166
      Location:43 → 237
      PTB_CCM2; Cerebral cavernous malformation 2 FERM domain C-lobe
      pfam16545
      Location:287 → 377
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology

    RNA

    1. NR_030770.2 RNA Sequence

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) represents use of an alternate promoter and 5' exon, compared to variant 1. This variant is represented as non-coding because it lacks the start codon of variant 1 and it is not clear what, if any, protein would be expressed from this variant.
      Source sequence(s)
      AC004847, AC013416, AI538498, DA420491
      Related
      ENST00000461377.5

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000007.14 Reference GRCh38.p14 Primary Assembly

      Range
      44999746..45076470
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047420889.1 → XP_047276845.1  cerebral cavernous malformations 2 protein isoform X6

      Related
      ENSP00000496916.1, ENST00000648329.1

    2. XM_011515561.3 → XP_011513863.1  cerebral cavernous malformations 2 protein isoform X1

      UniProtKB/TrEMBL
      A0A0A0MT72
      Conserved Domains (2) summary
      cd13166
      Location:64 → 258
      PTB_CCM2; Cerebral cavernous malformation 2 FERM domain C-lobe
      pfam16545
      Location:349 → 439
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology

    3. XM_006715786.4 → XP_006715849.1  cerebral cavernous malformations 2 protein isoform X4

      UniProtKB/TrEMBL
      C9JUH3
      Related
      ENSP00000419474.1, ENST00000474617.1
      Conserved Domains (2) summary
      pfam16545
      Location:217 → 307
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology
      cl17171
      Location:64 → 212
      PH-like; Pleckstrin homology-like domain

    4. XM_011515563.4 → XP_011513865.1  cerebral cavernous malformations 2 protein isoform X2

      UniProtKB/TrEMBL
      A0A0A0MT72
      Conserved Domains (2) summary
      cd13166
      Location:29 → 200
      PTB_CCM2; Cerebral cavernous malformation 2 FERM domain C-lobe
      pfam16545
      Location:291 → 381
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology

    5. XM_006715785.5 → XP_006715848.1  cerebral cavernous malformations 2 protein isoform X3

      UniProtKB/TrEMBL
      A0A0A0MT72
      Conserved Domains (2) summary
      cd13166
      Location:29 → 200
      PTB_CCM2; Cerebral cavernous malformation 2 FERM domain C-lobe
      pfam16545
      Location:250 → 340
      CCM2_C; Cerebral cavernous malformation protein, harmonin-homology

    6. XM_047420890.1 → XP_047276846.1  cerebral cavernous malformations 2 protein isoform X7

      Related
      ENSP00000417251.1, ENST00000488727.5

    7. XM_017012671.2 → XP_016868160.1  cerebral cavernous malformations 2 protein isoform X5

    8. XM_017012672.3 → XP_016868161.1  cerebral cavernous malformations 2 protein isoform X8

      UniProtKB/TrEMBL
      B7Z8D5
      Conserved Domains (1) summary
      cd13166
      Location:29 → 200
      PTB_CCM2; Cerebral cavernous malformation 2 FERM domain C-lobe

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060931.1 Alternate T2T-CHM13v2.0

      Range
      45160321..45237028
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9BSQ5.1 GenPept UniProtKB/Swiss-Prot:Q9BSQ5

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