HNRNPA2B1
protein-codingheterogeneous nuclear ribonucleoprotein A2/B1, the group of RNA binding motif containing|Heterogeneous nuclear ribonucleoproteins
Gene summary
This gene belongs to the A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. This gene has been described to generate two alternatively spliced transcript variants which encode different isoforms. [provided by RefSeq, Jul 2008]
- HNRPA2B1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~30.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0958195
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0004976
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014178
Submitter: ClinGen
*hnRNPA2B1* was first reported in relation to autosomal dominant inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (IBMPFD2) in 2013 (Kim HJ et al., PMID:23455423). IBMPFD2 families present with an incomplete penetrance of disabling muscle weakness in most cases, osteolytic bone lesions consistent with Paget disease in around half of cases, and frontotemporal dementia in a handful of cases. At least 5 variants, all missense, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in *hnRNPA2B1* have been reported in individuals with the following disease entities: amyotrophic lateral sclerosis, inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (IBMPFD2) and oculopharyngeal muscular dystrophy 2. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanism and inheritance pattern of amyotrophic lateral sclerosis and IBMPFD2. Therefore, the following disease entities have been lumped into one disease entity for this curation: amyotrophic lateral sclerosis (MONDO:0004976) and inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (OMIM:615422). The disease entity oculopharyngeal muscular dystrophy 2 (MONDO:0958195) has been split from this curation for difference in phenotype (especially ptosis and eye movement paralysis) and a distinct difference in molecular mechanism (frameshift variants that create the same novel amino acid series at the C-terminus of the protein). Variants in this gene have been reported in at least 5 probands in 5 publications (PMID:37528043, 25617006, 25299611, 28389692, 23455423). Variants in this gene segregated with disease in 10 additional family members across 2 families. This gene-disease relationship is supported by experimental evidence including biochemical function, protein interaction, functional alteration in both patient and non patient cells and a non-human model organism. Splicing sensitive microarrays showed that *hnRNPA2B1* has intrinsic properties that make it particularly susceptible to relocalization within the cell that may result in splicing defects when under stress (PMID:22574288). Protein interaction with TDP-53 (TARDBP), which has been previously implicated in this disease, is demonstrated in the literature (PMID:16157593). Functional alteration consistent with the disease has been demonstrated in patient cells (PMID: 27773581, 23455423) and HeLa cells (PMID: 23455423). Finally, a supporting drosophila model exists but has not been scored at full points as it is not a particularly strong model for this human disease (PMID: 23455423). This gene-disease pair was originally evaluated to have a limited gene-disease relationship by the Amyotrophic Lateral Sclerosis Spectrum Disorders Gene Curation Expert Panel on October 28, 2021. It was reevaluated on October 24, 2024. As a result of this reevaluation, the classification changed to a moderate gene-disease relationship. This classification change is due to a reevaluation of the lumping and splitting; the prior curation was completed with amyotrophic lateral sclerosis (MONDO:0004976) as the disease entity and in the re-curation the group has decided to lump amyotrophic lateral sclerosis and multisystem proteinopathy under the disease entity inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (MONDO:0014178). This lumping allowed both genetic and experimental evidence available at the time of the last curation, but excluded due to disease entity, to be scored. Since the original curation one more case has been added to the literature and is scored in this curation (PMID:37528043). This classification was approved by the ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders Gene Curation Expert Panel on the meeting date October 24, 2024 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0014178
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0000507
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014178
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008116
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
Intervention: General
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HNRNPA2B1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002137.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 103 | 3 | 110 | ||
| missense | 1 | 2 | 64 | 2 | 69 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 3 | 2 | 4 | 9 | ||
| splice donor/acceptor (+/-2bp) | 10 | 10 | ||||
| Total | 4 | 4 | 83 | 105 | 3 | 199 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002128.1 | 10 | MANE Select | |
| Ensembl | ENSP00000478691.2 | 10 | MANE Select | |
| RefSeq | NP_001424992.1 | 10 | Standard | |
| RefSeq | NP_001425497.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation
- mRNA Processing
- Metabolism of RNA
- mRNA Splicing - Major Pathway
- mRNA Splicing
Biological Process
- negative regulation of transcription by RNA polymerase II
- mRNA splicing, via spliceosome
- mRNA processing
- mRNA export from nucleus
- RNA metabolic process
Molecular Function
- RNA binding
- mRNA binding
- mRNA 3'-UTR binding
- protein binding
- miRNA binding
Cellular Component
- chromosome, telomeric region
- nucleus
- nucleoplasm
- spliceosomal complex
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000354667
- Coding exons
- 11
- Length
- 11603
- Individuals with no LoFs
- 125567
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125569
- p
- 0.00000796
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.00 | 75 | 192 | 0.390 | 0.00000925 | 2284 |
| Missense (PolyPhen) | 8 | 28.353 | 0.28216 | 383 | ||
| Synonymous | -5.37 | 118 | 63.6 | 1.86 | 0.00000330 | 651 |
| Loss of Function | 4.13 | 1 | 21.8 | 0.0459 | 0.00000100 | 291 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Heterogeneous nuclear ribonucleoprotein (hnRNP) that associates with nascent pre-mRNAs, packaging them into hnRNP particles. The hnRNP particle arrangement on nascent hnRNA is non- random and sequence-dependent and serves to condense and stabilize the transcripts and minimize tangling and knotting. Packaging plays a role in various processes such as transcription, pre-mRNA processing, RNA nuclear export, subcellular location, mRNA translation and stability of mature mRNAs (PubMed:19099192). Forms hnRNP particles with at least 20 other different hnRNP and heterogeneous nuclear RNA in the nucleus. Involved in transport of specific mRNAs to the cytoplasm in oligodendrocytes and neurons: acts by specifically recognizing and binding the A2RE (21 nucleotide hnRNP A2 response element) or the A2RE11 (derivative 11 nucleotide oligonucleotide) sequence motifs present on some mRNAs, and promotes their transport to the cytoplasm (PubMed:10567417). Specifically binds single-stranded telomeric DNA sequences, protecting telomeric DNA repeat against endonuclease digestion (By similarity). Also binds other RNA molecules, such as primary miRNA (pri-miRNAs): acts as a nuclear 'reader' of the N6-methyladenosine (m6A) mark by specifically recognizing and binding a subset of nuclear m6A-containing pri-miRNAs. Binding to m6A-containing pri- miRNAs promotes pri-miRNA processing by enhancing binding of DGCR8 to pri-miRNA transcripts (PubMed:26321680). Involved in miRNA sorting into exosomes following sumoylation, possibly by binding (m6A)-containing pre-miRNAs (PubMed:24356509). Acts as a regulator of efficiency of mRNA splicing, possibly by binding to m6A- containing pre-mRNAs (PubMed:26321680). {ECO:0000250|UniProtKB:A7VJC2, ECO:0000269|PubMed:10567417, ECO:0000269|PubMed:24356509, ECO:0000269|PubMed:26321680, ECO:0000303|PubMed:19099192}.;
- Disease
- DISEASE: Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (IBMPFD2) [MIM:615422]: An autosomal dominant disease characterized by disabling muscle weakness clinically resembling to limb girdle muscular dystrophy, osteolytic bone lesions consistent with Paget disease, and premature frontotemporal dementia. Clinical features show incomplete penetrance. {ECO:0000269|PubMed:23455423}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.230
Intolerance Scores
- LoFtool
- 0.121
- RVIS EVS
- -0.23
- RVIS percentile EVS
- 36.86
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.333
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |