POLR2A

protein-coding

RNA polymerase II subunit A, the group of RNA polymerase subunits

Gene summary

This gene encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a carboxy terminal domain composed of heptapeptide repeats that are essential for polymerase activity. These repeats contain serine and threonine residues that are phosphorylated in actively transcribing RNA polymerase. In addition, this subunit, in combination with several other polymerase subunits, forms the DNA binding domain of the polymerase, a groove in which the DNA template is transcribed into RNA. [provided by RefSeq, Jul 2008]

Previous symbols:

POLR2

MANE transcript

N/A

Inheritance

ClinVar variants

P:25U:226B:63

Top phenotype

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr17:7,484,366-7,514,616

External References & Databases

Ensembl (ENSG00000181222)

Transcript & Mutation Effects

hg38 • Region Span ~30.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032829

Submitter: Broad Center for Mendelian Genomics

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032829

Submitter: ClinGen

The POLR2A gene, encoding the largest subunit of RNA Pol II, was first reported in relation to autosomal dominant neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities in 2019 (Haijes et. al., PMID 31353023). The original curation contained 15 unique de novo missense or loss-of-function variants from a single publication (PMID:31353023). As a result of this re-evaluation, an additional 2 variants are included in the curation from a second publication (PMID: 33665635). More genetic evidence is available in the literature. The reported mechanism of disease for POLR2A variants range from mild haploinsufficiency to severe dominant-negative depending on variant location and consequence. This gene-disease relationship is supported by in vitro functional assays in yeast and HeLa cells showing reduced cell viability with specific patient variants (PMID 31353023). The gene-disease pair was originally evaluated by the Syndromic Disorders GCEP on August 5th, 2020 and was re-evaluated on March 15th, 2024. As a result of this re-evaluation, the classification increased from Moderate to Definitive with the addition of new published case reports (PMIDs: 33665635). This gene-disease relationship has now been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on March 15th, 2024 (SOP Version 10).

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032829

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032829

Submitter: Ambry Genetics

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032829

Submitter: PanelApp Australia

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032829

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLR2A variants in ClinVar

2 Conditions Cataloged

not providedTotal: 2

Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalitiesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript . 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			2 clinvar	50 clinvar	5 clinvar	57
missense	2 clinvar	17 clinvar	208 clinvar	7 clinvar		234
nonsense	1 clinvar	3 clinvar	5 clinvar			9
start loss						0
frameshift		2 clinvar	8 clinvar		1 clinvar	11
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	3	22	226	57	6	314

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000937.5	RefSeq	NP_000928.1	30	Standard
ENST00000674977.2	Ensembl	ENSP00000502190.2	30	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyrimidine metabolism - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
RNA polymerase - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Epstein-Barr virus infection - Homo sapiens (human)

Biological Process

mRNA splicing, via spliceosome
transcription, RNA-templated
transcription-coupled nucleotide-excision repair
DNA-templated transcription, termination
regulation of transcription, DNA-templated

Molecular Function

RNA polymerase II activity
DNA binding
RNA binding
DNA-directed 5'-3' RNA polymerase activity
RNA-directed 5'-3' RNA polymerase activity

Cellular Component

Prp19 complex
nucleus
nucleoplasm
RNA polymerase II, core complex
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000322644
Coding exons: 29
Length: 30249
Individuals with no LoFs: 125697
Homozygous LoFs: 0
Heterozygous LoFs: 51
Defined: 125748
p: 0.000203

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	7.13	512	1.21e+3	0.423	0.0000769	12800
Missense (PolyPhen)		107	521.33	0.20524		5326
Synonymous	-5.06	625	483	1.29	0.0000317	4039
Loss of Function	7.72	7	82.8	0.0846	0.00000481	959

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00014	0.000062	rare
Latino/Admixed American	0.00015	0.00012	rare
Ashkenazi Jewish	0.00040	0.00030	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00065	0.00032	rare
European (Non-Finnish)	0.00044	0.00027	rare
South Asian	0.000033	0.000033	rare
Other	0.00083	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Forms the polymerase active center together with the second largest subunit. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB1 is part of the core element with the central large cleft, the clamp element that moves to open and close the cleft and the jaws that are thought to grab the incoming DNA template. At the start of transcription, a single-stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol II. A bridging helix emanates from RPB1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol II by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition. During transcription elongation, Pol II moves on the template as the transcript elongates. Elongation is influenced by the phosphorylation status of the C-terminal domain (CTD) of Pol II largest subunit (RPB1), which serves as a platform for assembly of factors that regulate transcription initiation, elongation, termination and mRNA processing. Regulation of gene expression levels depends on the balance between methylation and acetylation levels of tha CTD-lysines (By similarity). Initiation or early elongation steps of transcription of growth-factors- induced immediate early genes are regulated by the acetylation status of the CTD (PubMed:24207025). Methylation and dimethylation have a repressive effect on target genes expression (By similarity). {ECO:0000250|UniProtKB:P08775, ECO:0000269|PubMed:20231364, ECO:0000269|PubMed:23748380, ECO:0000269|PubMed:24207025, ECO:0000269|PubMed:9852112}.;

Recessive Scores

pRec: 0.572

Intolerance Scores

LoFtool: 0.260
RVIS EVS: -3.52
RVIS percentile EVS: 0.32

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.850

Gene Damage Prediction

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