GeneBe

RNASEH2B

protein-coding

ribonuclease H2 subunit B

Gene summary

RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits (B and C) and specifically degrades the RNA of RNA:DNA hybrids. The protein encoded by this gene is the non-catalytic B subunit of RNase H2, which is thought to play a role in DNA replication. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Aicardi-Goutieres syndrome type 2 (AGS2). [provided by RefSeq, Nov 2008]

Previous symbols:
  • DLEU8
  • AGS2

MANE transcript

NM_024570.4

Inheritance

AD, AR

ClinVar variants

P:71U:171B:115

Top phenotype

Aicardi-Goutieres syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.81

Max pathogenic AF

—

Genomic locus

chr13:50,909,747-51,024,120

External References & Databases

Ensembl (ENSG00000136104)NCBI Gene (79621)OMIM (610326)HGNC:25671GenCCUniProt (Q5TBB1)AlphaFoldClinVar (RNASEH2B)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~114.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

prostate cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008315

Submitter: Ambry Genetics

Aicardi-Goutieres syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012429

Submitter: Labcorp Genetics (formerly Invitae)

Aicardi-Goutieres syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012429

Submitter: PanelApp Australia

RNASEH2B-related type 1 interferonopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0700257

Submitter: ClinGen

RNASEH2B-related Type 1 Interferonopathy, Autosomal Recessive RNASEH2B was first reported in relation to autosomal recessive Aicardi-Goutieres syndrome type 2 (OMIM: 610326) in 2006 (PMID: 16845400). RNASEH2B encodes the ribonuclease H2 subunit B, which comprises 308 amino acids. RNASEH enzymes endolytically cleave ribonucleotides from RNA:DNA duplexes, which occur during DNA replication, transcription and translation. RNASEH2 has been proposed to function in the removal of lagging strand Okazaki fragment RNA primers during DNA replication, as well as in the excision of single ribonucleotides from RNA:DNA duplexes (PMIDs: 21177854, 16845400). The described autosomal recessive RNASEH2B phenotype is considered to be a form of type 1 interferonopathy, which is defined as a condition in which increased type 1 interferon signaling leads to autoimmune and neurological disorders (MONDO: 0700257). These disorders are caused by variants in genes involved in nucleic acid metabolism, sensing, and the innate immune response. Individuals with biallelic variants in RNASEH2B can present with a range of symptoms of variable severity and age of onset, within the context of an autoimmune disease. At least 10 unique variants (missense, splicing, nonsense) have been reported across 13 probands in 6 publications (PMIDs: 33981319, 33307271, 36775013, 22882256, 39183359, 25604658) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is thought to be loss of function. This gene-disease relationship is also supported by experimental evidence (model system studies, PMIDs: 34655526, 26903602). A study by Aditi et al., 2021 generated a murine model of neural Rnaseh2b inactivation (Rnaseh2bNes-cre), which demonstrated cerebellar atrophy, loss of granule neurons and interneurons, thinning of the corpus callosum, loss of oligodendrocytes, and white matter abnormalities. A study by Mackenzie et al., 2016 generated a murine model by knock-in of the A174T missense variant (c.520A>G) into exon 7 of Rnaseh2b in mouse embryonic stem cells, which demonstrated reduced cellular levels of all three RNase H2 subunits and demonstrated significant interferon-stimulated gene (ISG) transcript upregulation that recapitulated the ISG signature observed in RNase H2 AGS patients. In summary, there is definitive evidence supporting the relationship between RNASEH2B and autosomal recessive RNASEH2B-related type 1 interferonopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic setting, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date November 20, 2024 (SOP Version 11).

Aicardi-Goutieres syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018866

Submitter: Orphanet

Aicardi-Goutieres syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012429

Submitter: G2P

Aicardi-Goutieres syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012429

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Aicardi-Goutieres syndrome 2AR

Manifestation: Cardiovascular; Gastrointestinal; Dermatologic; Hematologic; 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

Refs: 9706629; 16845400; 20301648; 25243380Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNASEH2B variants in ClinVar

13 Conditions Cataloged
Aicardi-Goutieres syndrome 2Total: 481
not providedTotal: 58
Inborn genetic diseasesTotal: 43
not specifiedTotal: 39
RNASEH2B-related disorderTotal: 21
Aicardi Goutieres syndromeTotal: 6
Autism spectrum disorderTotal: 2
Hereditary spastic paraplegiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024570.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
106
clinvar
1
clinvar
 110
missense
10
clinvar
149
clinvar
7
clinvar
 166
nonsense
13
clinvar
4
clinvar
1
clinvar
 18
start loss
1
clinvar
2
clinvar
 3
frameshift
16
clinvar
6
clinvar
10
clinvar
1
clinvar
 33
splice donor/acceptor (+/-2bp)
2
clinvar
17
clinvar
8
clinvar
 27
Total32391711141357

Highest pathogenic variant AF is 0.002016424

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 94 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_024570.4RefSeqNP_078846.211MANE Select
ENST00000336617.8EnsemblENSP00000337623.211MANE Select
NM_001142279.2RefSeqNP_001135751.110Standard
NM_001411023.1RefSeqNP_001397952.111Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • DNA replication - Homo sapiens (human)

Biological Process

  • in utero embryonic development
  • RNA catabolic process
  • ribonucleotide metabolic process
  • regulation of G2/M transition of mitotic cell cycle
  • negative regulation of gene expression

Molecular Function

  • RNA-DNA hybrid ribonuclease activity

Cellular Component

  • nucleus
  • nucleoplasm
  • ribonuclease H2 complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000336617
Coding exons
11
Length
60779
Individuals with no LoFs
125708
Homozygous LoFs
0
Heterozygous LoFs
40
Defined
125748
p
0.000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.2391541461.060.000006662039
Missense (PolyPhen)4643.3561.061644
Synonymous-0.2285350.91.040.00000231545
Loss of Function0.7601518.50.8107.76e-7266

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000310.00031rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.000220.00020rare
South Asian0.000130.00013rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids. Participates in DNA replication, possibly by mediating the removal of lagging- strand Okazaki fragment RNA primers during DNA replication. Mediates the excision of single ribonucleotides from DNA:RNA duplexes. {ECO:0000269|PubMed:16845400, ECO:0000269|PubMed:21177858}.;

Intolerance Scores

LoFtool
0.193
RVIS EVS
0.04
RVIS percentile EVS
56.92

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
N
Indispensability score
0.275

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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