RNASEH2C

protein-coding

ribonuclease H2 subunit C

Gene summary

This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_032193.4

Inheritance

AD, AR

ClinVar variants

P:12U:147B:110

Top phenotype

Aicardi-Goutieres syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr11:65,714,005-65,720,818

External References & Databases

Ensembl (ENSG00000172922)

Transcript & Mutation Effects

hg38 • Region Span ~6.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Aicardi-Goutieres syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018866

Submitter: Orphanet

Aicardi-Goutieres syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012471

Submitter: G2P

Aicardi-Goutieres syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012471

Submitter: Labcorp Genetics (formerly Invitae)

RNASEH2C-related type 1 interferonopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0700258

Submitter: ClinGen

RNASEH2C was first reported in relation to autosomal recessive Aicardi-Goutieres type 3 (OMIM: 610330) in 2006 (PMID: 16845400). RNASEH2C encodes ribonuclease H2 subunit C, which comprises 164 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 DNA:DNA duplexes (PMIDs: 21177854, 16845400). The described autosomal recessive RNASEH2C 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: 0700258). These disorders are caused by variants in genes involved in nucleic acid metabolism, sensing, and the innate immune response. Individuals with biallelic variants in RNASEH2C can present with a range of symptoms of variable severity and age of onset, within the context of an autoimmune disease. At least 16 unique variants (missense, splicing, nonsense, indel) have been reported across 15 probands in 7 publications (PMIDs: 31130681, 23322642, 35551623, 16845400, 31559893, 25604658, 24183309) 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, PMID: 22802351). Although the mouse phenotype was limited due to early embryonic lethality, cells obtained from knock-out mouse embryos demonstrated increased genomic ribonucleotide load consistent with the underlying disease mechanism for type 1 interferonopathy (PMID: 22802351). In summary, there is definitive evidence supporting the relationship between RNASEH2C and autosomal recessive RNASEH2C-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 approached by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date July 10, 2024 (SOP Version 10).

Aicardi-Goutieres syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012471

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Aicardi-Goutieres syndrome 3AR

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: 16845400; 17846997; 20301648; 23322642

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNASEH2C variants in ClinVar

7 Conditions Cataloged

Aicardi-Goutieres syndrome 3Total: 315

not providedTotal: 40

Inborn genetic diseasesTotal: 36

not specifiedTotal: 27

RNASEH2C-related disorderTotal: 13

Aicardi Goutieres syndromeTotal: 4

Abnormality of the nervous systemTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032193.4. 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			1 clinvar	106 clinvar	2 clinvar	109
missense	1 clinvar	7 clinvar	137 clinvar	2 clinvar		147
nonsense		3 clinvar				3
start loss						0
frameshift		1 clinvar	8 clinvar			9
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	11	147	108	2	269

Highest pathogenic variant AF is 0.000037794864

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032193.4	RefSeq	NP_115569.2	4	MANE Select
ENST00000308418.10	Ensembl	ENSP00000308193.5	4	MANE Select
ENST00000527610.1	Ensembl	ENSP00000432897.1	3	Standard
ENST00000531596.6	Ensembl	ENSP00000435717.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

DNA replication - Homo sapiens (human)

Biological Process

RNA catabolic process

Cellular Component

nucleus
ribonuclease H2 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000308418
Coding exons: 4
Length: 6052
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.917	122	96.6	1.26	0.00000463	1037
Missense (PolyPhen)		38	34.385	1.1051		370
Synonymous	-1.41	54	42.3	1.28	0.00000219	356
Loss of Function	0.791	4	6.11	0.655	2.73e-7	69

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000060	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000063	0.000062	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

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}.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.277
RVIS EVS: -0.05
RVIS percentile EVS: 49.39

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.910

Gene Damage Prediction

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