POLG2

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

Basic information

Region (hg38): 17:64477784-64497054

Links

ENSG00000256525 ∙ NCBI:11232 ∙ OMIM:604983 ∙ HGNC:9180 ∙ Uniprot:Q9UHN1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mitochondrial DNA depletion syndrome 16 (hepatic type) (Limited), mode of inheritance: AR
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (Limited), mode of inheritance: AD
• autosomal dominant progressive external ophthalmoplegia (Supportive), mode of inheritance: AD
• mitochondrial DNA depletion syndrome (Moderate), mode of inheritance: Semidominant
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4; Mitochondrial DNA depletion syndrome 16; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type)	AD/AR	General	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	Biochemical; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic	12975295; 15351195; 16685652; 20405137; 22155748; 27592148; 30157269; 31778857

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the POLG2 gene.

• not provided (313 variants)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (34 variants)
• not specified (26 variants)
• Hereditary spastic paraplegia (14 variants)
• Inborn genetic diseases (12 variants)
• Mitochondrial DNA depletion syndrome 16 (hepatic type) (5 variants)
• Mitochondrial dna depletion syndrome 16B (neuroophthalmic type) (3 variants)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions (2 variants)
• POLG2-Related Disorders (2 variants)
• Acute liver failure (1 variants)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4;Mitochondrial DNA depletion syndrome 16 (hepatic type);Mitochondrial dna depletion syndrome 16B (neuroophthalmic type) (1 variants)
• Mitochondrial DNA depletion syndrome 16A (1 variants)
• POLG2-related spectrum disorders (1 variants)
• Mitochondrial DNA depletion syndrome 16 (hepatic type);Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the POLG2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	57	3	66
missense		2	159	4	2	167
nonsense	3		3			6
start loss			2			2
frameshift	8	1	4			13
inframe indel			2			2
splice donor/acceptor (+/-2bp)		4	2			6
splice region			5	5	1	11
non coding			4	27	12	43
Total	11	7	182	88	17

Highest pathogenic variant AF is 0.0000197

Variants in POLG2

This is a list of pathogenic ClinVar variants found in the POLG2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
17-64477825-A-G			Uncertain significance (Aug 10, 2023)
17-64477836-G-A			Uncertain significance (Jul 11, 2022)
17-64477837-C-A		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	Uncertain significance (Oct 05, 2022)
17-64477846-T-C			Uncertain significance (Nov 22, 2022)
17-64477850-C-T			Likely benign (Nov 24, 2023)
17-64477856-CAA-C		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	Pathogenic (Aug 01, 2011)
17-64477864-C-T		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 • Hereditary spastic paraplegia	Conflicting classifications of pathogenicity (Jan 27, 2024)
17-64477880-A-G			Likely benign (Nov 17, 2023)
17-64477895-C-T			Uncertain significance (Aug 17, 2022)
17-64477897-T-C			Uncertain significance (Aug 09, 2022)
17-64477900-T-C			Uncertain significance (Nov 07, 2023)
17-64477916-C-A			Likely benign (Jan 26, 2022)
17-64477918-G-T		Hereditary spastic paraplegia	Uncertain significance (Feb 14, 2023)
17-64477929-C-T		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 • POLG2-related disorder	Likely pathogenic (Aug 23, 2023)
17-64477930-C-G			Uncertain significance (May 02, 2023)
17-64477932-T-G			Uncertain significance (Sep 22, 2023)
17-64477933-TCTCCA-T		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	Uncertain significance (Oct 11, 2018)
17-64477935-T-G			Uncertain significance (Apr 06, 2022)
17-64477937-C-A			Uncertain significance (Jan 01, 2022)
17-64477941-G-C			Uncertain significance (Jul 26, 2022)
17-64477942-T-C			Uncertain significance (Apr 17, 2023)
17-64477952-A-G			Likely benign (Dec 24, 2023)
17-64477957-A-C			Uncertain significance (Oct 30, 2017)
17-64477962-G-A			Uncertain significance (Nov 09, 2022)
17-64477964-G-A			Likely benign (Dec 04, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
POLG2	protein_coding	protein_coding	ENST00000539111	8	19253

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.53e-10	0.583	125668	0	80	125748	0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.347	270	254	1.06	0.0000122	3155
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000539	0.000539
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000163	0.000163
Finnish	0.000418	0.000416
European (Non-Finnish)	0.000387	0.000378
Middle Eastern	0.000163	0.000163
South Asian	0.000327	0.000327
Other	0.000163	0.000163

dbNSFP

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.
• Pathway: Mitochondrial biogenesis;Purine metabolism;Pyrimidine metabolism (Consensus)

Recessive Scores

• pRec: 0.124

Intolerance Scores

• loftool: 0.383
• rvis_EVS: 0.09
• rvis_percentile_EVS: 60.47

Haploinsufficiency Scores

• pHI: 0.248
• hipred: N
• hipred_score: 0.221
• ghis: 0.550

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.695

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Polg2
• Phenotype: embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; cellular phenotype

Gene ontology

• Biological process: in utero embryonic development;DNA replication;DNA-dependent DNA replication;mitochondrial DNA replication;DNA repair;mitochondrion organization;respiratory electron transport chain;mitochondrion morphogenesis;DNA biosynthetic process
• Cellular component: mitochondrial chromosome;cytoplasm;mitochondrion;mitochondrial matrix;mitochondrial nucleoid
• Molecular function: DNA binding;DNA-directed DNA polymerase activity;protein binding;identical protein binding