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    CACNA2D1 calcium voltage-gated channel auxiliary subunit alpha2delta 1 [ Homo sapiens (human) ]

    Gene ID: 781, updated on 10-Dec-2024

    Summary

    Official Symbol
    CACNA2D1provided by HGNC
    Official Full Name
    calcium voltage-gated channel auxiliary subunit alpha2delta 1provided by HGNC
    Primary source
    HGNC:HGNC:1399
    See related
    Ensembl:ENSG00000153956 MIM:114204; AllianceGenome:HGNC:1399
    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
    CACNA2; CCHL2A; DEE110; CACNL2A; LINC01112; lncRNA-N3
    Summary
    The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]
    Expression
    Broad expression in brain (RPKM 8.0), heart (RPKM 5.6) and 21 other tissues See more
    Orthologs
    NEW
    Try the new Gene table
    Try the new Transcript table

    Genomic context

    See CACNA2D1 in Genome Data Viewer
    Location:
    7q21.11
    Exon count:
    44
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 7 NC_000007.14 (81946444..82443956, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 7 NC_060931.1 (83197632..83695210, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 7 NC_000007.13 (81575760..82073272, complement)

    Chromosome 7 - NC_000007.14Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC100128317 Neighboring gene P300/CBP strongly-dependent group 1 enhancer GRCh37_chr7:81252185-81253384 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr7:81302077-81302610 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_100136 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 18335 Neighboring gene DEAD-box helicase 43 pseudogene 3 Neighboring gene hepatocyte growth factor Neighboring gene ATAC-STARR-seq lymphoblastoid active region 26211 Neighboring gene P300/CBP strongly-dependent group 1 enhancer GRCh37_chr7:81487648-81488847 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 26212 Neighboring gene CACNA2D1 antisense RNA 1 Neighboring gene uncharacterized LOC124901687 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr7:81914122-81914773 Neighboring gene uncharacterized LOC107986813 Neighboring gene uncharacterized LOC124901688 Neighboring gene VISTA enhancer hs2419 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr7:82071535-82072098 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr7:82100858-82102057 Neighboring gene OCT4-NANOG-H3K4me1 hESC enhancer GRCh37_chr7:82133878-82134458 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr7:82135692-82136192 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr7:82267896-82268556 Neighboring gene methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase pseudogene 5 Neighboring gene uncharacterized LOC105375376

    Genomic regions, transcripts, and products

    Expression

    • Project title: Tissue-specific circular RNA induction during human fetal development
    • Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
    • BioProject: PRJNA270632
    • Publication: PMID 26076956
    • Analysis date: Mon Apr 2 22:54:59 2018

    Bibliography

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?

    Phenotypes

    Associated conditions

    Description Tests
    Developmental and epileptic encephalopathy 110
    MedGen: C5774265 OMIM: 620149 GeneReviews: Not available
    not available

    EBI GWAS Catalog

    Description
    A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder.
    EBI GWAS Catalog
    Genetic association with overall survival of taxane-treated lung cancer patients - A genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study.
    EBI GWAS Catalog
    Genetic predictors of medically refractory ulcerative colitis.
    EBI GWAS Catalog
    Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease.
    EBI GWAS Catalog
    Genome-wide association study of a heart failure related metabolomic profile among African Americans in the Atherosclerosis Risk in Communities (ARIC) study.
    EBI GWAS Catalog
    Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.
    EBI GWAS Catalog
    Multidimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn's disease.
    EBI GWAS Catalog
    Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population.
    EBI GWAS Catalog

    Pathways from PubChem

    Interactions

    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

    Markers

    Clone Names

    • FLJ30478

    Gene Ontology Provided by GOA

    Process Evidence Code Pubs
    involved_in calcium ion import across plasma membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in calcium ion transmembrane transport via high voltage-gated calcium channel ISS
    Inferred from Sequence or Structural Similarity
    more info
    PubMed 
    involved_in calcium ion transport IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in calcium ion transport into cytosol ISS
    Inferred from Sequence or Structural Similarity
    more info
    PubMed 
    involved_in cardiac muscle cell action potential involved in contraction IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in cellular response to amyloid-beta IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in membrane depolarization during bundle of His cell action potential IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in regulation of calcium ion transmembrane transport via high voltage-gated calcium channel IGI
    Inferred from Genetic Interaction
    more info
    PubMed 
    involved_in regulation of calcium ion transport IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in regulation of heart rate by cardiac conduction IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in regulation of membrane repolarization during action potential ISS
    Inferred from Sequence or Structural Similarity
    more info
    PubMed 
    involved_in regulation of ventricular cardiac muscle cell membrane repolarization IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    Component Evidence Code Pubs
    located_in GABA-ergic synapse IEA
    Inferred from Electronic Annotation
    more info
     
    part_of L-type voltage-gated calcium channel complex IBA
    Inferred from Biological aspect of Ancestor
    more info
     
    part_of L-type voltage-gated calcium channel complex IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in extracellular exosome HDA PubMed 
    located_in neuronal dense core vesicle IEA
    Inferred from Electronic Annotation
    more info
     
    located_in plasma membrane IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in presynaptic active zone membrane IEA
    Inferred from Electronic Annotation
    more info
     
    located_in sarcoplasmic reticulum IEA
    Inferred from Electronic Annotation
    more info
     
    part_of voltage-gated calcium channel complex IDA
    Inferred from Direct Assay
    more info
    PubMed 

    General protein information

    Preferred Names
    voltage-dependent calcium channel subunit alpha-2/delta-1
    Names
    alpha2delta-1
    calcium channel, L type, alpha 2 polypeptide
    calcium channel, voltage-dependent, alpha 2/delta subunit 1
    dihydropyridine-sensitive L-type, calcium channel alpha-2/delta subunit
    voltage-gated calcium channel subunit alpha-2/delta-1

    NCBI Reference Sequences (RefSeq)

    NEW Try the new Transcript table

    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_009358.2 RefSeqGene

      Range
      4910..502272
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_437

    mRNA and Protein(s)

    1. NM_000722.4NP_000713.2  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform 1 preproprotein

      See identical proteins and their annotated locations for NP_000713.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AC006145, AI924415, AL707206, AL833141, BC051339, BG055272, BP258070, M76559
      Consensus CDS
      CCDS5598.1
      UniProtKB/TrEMBL
      A0A994J595
      Related
      ENSP00000349320.3, ENST00000356860.8
      Conserved Domains (5) summary
      cd01463
      Location:239417
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:446531
      Cache_1; Cache domain
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      pfam08473
      Location:543627
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
      cl21471
      Location:636816
      RAMP_I_III; CRISPR/Cas system-associated RAMP superfamily protein
    2. NM_001302890.2NP_001289819.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform 2 precursor

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks multiple 3' exons and contains an alternate 3' coding region and 3' UTR, compared to variant 1. The encoded isoform (2) has a distinct C-terminus and is shorter than isoform 1. This isoform lacks the entire delta chain and a large portion of the alpha-2 chain.
      Source sequence(s)
      BC051339, BP258070
      Consensus CDS
      CCDS78253.1
      UniProtKB/TrEMBL
      E7ERK3
      Related
      ENSP00000405395.1, ENST00000423588.1
      Conserved Domains (2) summary
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      cl00057
      Location:239300
      vWFA; Von Willebrand factor type A (vWA) domain was originally found in the blood coagulation protein von Willebrand factor (vWF). Typically, the vWA domain is made up of approximately 200 amino acid residues folded into a classic a/b para-rossmann type of ...
    3. NM_001366867.1NP_001353796.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform 3 preproprotein

      Status: REVIEWED

      Source sequence(s)
      AC004970, AC004989, AC006145, AC008283
      Consensus CDS
      CCDS94135.1
      UniProtKB/Swiss-Prot
      P54289, Q17R45, Q9UD80, Q9UD81, Q9UD82
      UniProtKB/TrEMBL
      A0A994J595
      Related
      ENSP00000409374.2, ENST00000443883.2
      Conserved Domains (4) summary
      cd01463
      Location:239417
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:425530
      dCache_1; Cache domain
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      pfam08473
      Location:6451072
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    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
      81946444..82443956 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_005250574.4XP_005250631.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X10

      UniProtKB/TrEMBL
      A0A994J595
      Related
      ENSP00000516190.1, ENST00000705962.1
      Conserved Domains (5) summary
      cd01463
      Location:239417
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:446530
      Cache_1; Cache domain
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      pfam08473
      Location:538622
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
      cl21471
      Location:537804
      RAMP_I_III; CRISPR/Cas system-associated RAMP superfamily protein
    2. XM_005250572.4XP_005250629.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X6

      UniProtKB/TrEMBL
      A0A994J595
      Conserved Domains (5) summary
      cd01463
      Location:239417
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:446530
      Cache_1; Cache domain
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      pfam08473
      Location:538622
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
      cl21471
      Location:631811
      RAMP_I_III; CRISPR/Cas system-associated RAMP superfamily protein
    3. XM_005250573.4XP_005250630.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X8

      UniProtKB/TrEMBL
      A0A994J595
      Conserved Domains (5) summary
      cd01463
      Location:239417
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:446531
      Cache_1; Cache domain
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      pfam08473
      Location:543627
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
      cl21471
      Location:542809
      RAMP_I_III; CRISPR/Cas system-associated RAMP superfamily protein
    4. XM_011516572.4XP_011514874.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X5

      UniProtKB/TrEMBL
      A0A994J595
      Conserved Domains (5) summary
      cd01463
      Location:239417
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:446536
      Cache_1; Cache domain
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      pfam08473
      Location:557641
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
      cl21471
      Location:556823
      RAMP_I_III; CRISPR/Cas system-associated RAMP superfamily protein
    5. XM_011516571.4XP_011514873.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X3

      UniProtKB/TrEMBL
      A0A994J595
      Conserved Domains (5) summary
      cd01463
      Location:239417
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:446536
      Cache_1; Cache domain
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      pfam08473
      Location:557641
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
      cl21471
      Location:650830
      RAMP_I_III; CRISPR/Cas system-associated RAMP superfamily protein
    6. XM_006716118.4XP_006716181.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X1

      See identical proteins and their annotated locations for XP_006716181.1

      UniProtKB/TrEMBL
      A0A994J595, Q9UIU0
      Conserved Domains (5) summary
      cd01463
      Location:239417
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:446536
      Cache_1; Cache domain
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      pfam08473
      Location:562646
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
      cl21471
      Location:655835
      RAMP_I_III; CRISPR/Cas system-associated RAMP superfamily protein
    7. XM_006716120.4XP_006716183.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X12

      UniProtKB/TrEMBL
      A0A994J595
      Related
      ENSP00000516189.1, ENST00000705961.1
      Conserved Domains (4) summary
      cd01463
      Location:200378
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:407497
      Cache_1; Cache domain
      pfam08399
      Location:65184
      VWA_N; VWA N-terminal
      pfam08473
      Location:523607
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
    8. XM_006716121.3XP_006716184.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X13

      Conserved Domains (2) summary
      pfam08473
      Location:32116
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
      cl21471
      Location:125305
      RAMP_I_III; CRISPR/Cas system-associated RAMP superfamily protein
    9. XM_047420822.1XP_047276778.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X11

      UniProtKB/TrEMBL
      A0A994J595
    10. XM_047420820.1XP_047276776.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X7

      UniProtKB/TrEMBL
      A0A994J595
    11. XM_047420821.1XP_047276777.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X9

      UniProtKB/TrEMBL
      A0A994J595
    12. XM_047420819.1XP_047276775.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X4

      UniProtKB/TrEMBL
      A0A994J595
    13. XM_011516570.4XP_011514872.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X2

      UniProtKB/TrEMBL
      A0A994J595
      Conserved Domains (5) summary
      cd01463
      Location:239417
      vWA_VGCC_like; VWA Voltage gated Calcium channel like: Voltage-gated calcium channels are a complex of five proteins: alpha 1, beta 1, gamma, alpha 2 and delta. The alpha 2 and delta subunits result from proteolytic processing of a single gene product and carries at ...
      pfam02743
      Location:446536
      Cache_1; Cache domain
      pfam08399
      Location:104223
      VWA_N; VWA N-terminal
      pfam08473
      Location:562646
      VGCC_alpha2; Neuronal voltage-dependent calcium channel alpha 2acd
      cl21471
      Location:655835
      RAMP_I_III; CRISPR/Cas system-associated RAMP superfamily protein

    RNA

    1. XR_001744873.3 RNA Sequence

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060931.1 Alternate T2T-CHM13v2.0

      Range
      83197632..83695210 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054358980.1XP_054214955.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X10

      UniProtKB/TrEMBL
      A0A994J595
    2. XM_054358975.1XP_054214950.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X6

      UniProtKB/TrEMBL
      A0A994J595
    3. XM_054358978.1XP_054214953.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X8

      UniProtKB/TrEMBL
      A0A994J595
    4. XM_054358974.1XP_054214949.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X5

      UniProtKB/TrEMBL
      A0A994J595
    5. XM_054358972.1XP_054214947.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X3

      UniProtKB/TrEMBL
      A0A994J595
    6. XM_054358970.1XP_054214945.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X1

      UniProtKB/TrEMBL
      A0A994J595, Q9UIU0
    7. XM_054358982.1XP_054214957.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X12

      UniProtKB/TrEMBL
      A0A994J595
    8. XM_054358977.1XP_054214952.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X14

      UniProtKB/TrEMBL
      A0A994J595
    9. XM_054358983.1XP_054214958.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X13

    10. XM_054358981.1XP_054214956.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X11

      UniProtKB/TrEMBL
      A0A994J595
    11. XM_054358976.1XP_054214951.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X7

      UniProtKB/TrEMBL
      A0A994J595
    12. XM_054358973.1XP_054214948.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X4

      UniProtKB/TrEMBL
      A0A994J595
    13. XM_054358971.1XP_054214946.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X2

      UniProtKB/TrEMBL
      A0A994J595
    14. XM_054358979.1XP_054214954.1  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X9

      UniProtKB/TrEMBL
      A0A994J595

    RNA

    1. XR_008487750.1 RNA Sequence