POLG2

protein-coding

DNA polymerase gamma 2, accessory subunit, the group of DNA polymerases

Gene summary

This gene encodes the processivity subunit of the mitochondrial DNA polymerase gamma. The encoded protein forms a heterotrimer containing one catalytic subunit and two processivity subunits. This protein enhances DNA binding and promotes processive DNA synthesis. Mutations in this gene result in autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions.[provided by RefSeq, Sep 2009]

MANE transcript

NM_007215.4

Inheritance

AR, AD, SD

ClinVar variants

P:41U:315B:132

Top phenotype

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4; Mitochondrial DNA depletion syndrome 16; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type)

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr17:64,477,785-64,497,054

External References & Databases

Ensembl (ENSG00000256525)

Transcript & Mutation Effects

hg38 • Region Span ~19.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial DNA depletion syndrome 16 (hepatic type)LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032799

Submitter: Ambry Genetics

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012415

Submitter: Labcorp Genetics (formerly Invitae)

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012415

Submitter: Ambry Genetics

autosomal dominant progressive external ophthalmoplegiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008003

Submitter: Orphanet

mitochondrial DNA depletion syndromeMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0018158

Submitter: Illumina

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012415

Submitter: PanelApp Australia

mitochondrial dna depletion syndrome 16B (neuroophthalmic type)MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030326

Submitter: PanelApp Australia

mitochondrial DNA depletion syndrome 16 (hepatic type)MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032799

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4; Mitochondrial DNA depletion syndrome 16; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type)AD/AR

Manifestation: Biochemical; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic

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: 12975295; 15351195; 16685652; 20405137; 22155748; 27592148; 30157269; 31778857

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLG2 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 510

not specifiedTotal: 101

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4Total: 35

POLG2-related disorderTotal: 21

Hereditary spastic paraplegiaTotal: 14

Mitochondrial DNA depletion syndrome 16 (hepatic type)Total: 7

Mitochondrial dna depletion syndrome 16B (neuroophthalmic type)Total: 6

Hereditary skeletal muscle disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007215.4. 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			3 clinvar	107 clinvar		110
missense	1 clinvar	2 clinvar	293 clinvar	24 clinvar	1 clinvar	321
nonsense	6 clinvar	8 clinvar	4 clinvar			18
start loss			3 clinvar			3
frameshift	14 clinvar	2 clinvar	9 clinvar			25
splice donor/acceptor (+/-2bp)		8 clinvar	3 clinvar			11
Total	21	20	315	131	1	488

Highest pathogenic variant AF is 0.000046471454

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007215.4	RefSeq	NP_009146.2	8	MANE Select
ENST00000539111.7	Ensembl	ENSP00000442563.2	8	MANE Select
ENST00000578997.1	Ensembl	ENSP00000464389.1	2	Standard
ENST00000581355.1	Ensembl	ENSP00000462071.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mitochondrial biogenesis
Purine metabolism
Pyrimidine metabolism

Biological Process

in utero embryonic development
DNA replication
DNA-dependent DNA replication
mitochondrial DNA replication
DNA repair

Molecular Function

DNA binding
DNA-directed DNA polymerase activity
protein binding
identical protein binding

Cellular Component

mitochondrial chromosome
cytoplasm
mitochondrion
mitochondrial matrix
mitochondrial nucleoid

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000539111
Coding exons: 8
Length: 19253
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 80
Defined: 125748
p: 0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.347	270	254	1.06	0.0000122	3155
Missense (PolyPhen)		84	83.417	1.007		1038
Synonymous	-0.345	103	98.6	1.04	0.00000478	947
Loss of Function	1.32	19	26.3	0.721	0.00000156	284

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00039	0.00038	rare
South Asian	0.00033	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mitochondrial polymerase processivity subunit. Stimulates the polymerase and exonuclease activities, and increases the processivity of the enzyme. Binds to ss-DNA.;
Disease: DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 4 (PEOA4) [MIM:610131]: A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. {ECO:0000269|PubMed:16685652}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.124

Intolerance Scores

LoFtool: 0.383
RVIS EVS: 0.09
RVIS percentile EVS: 60.47

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.695

Gene Damage Prediction

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