DNA2

DNA replication helicase/nuclease 2, the group of UPF1 like RNA helicases

Basic information

Region (hg38): 10:68414064-68472121

Previous symbols: [ "DNA2L" ]

Links

ENSG00000138346 ∙ NCBI:1763 ∙ OMIM:601810 ∙ HGNC:2939 ∙ Uniprot:P51530 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Seckel syndrome 8 (Limited), mode of inheritance: AR
• Seckel syndrome 8 (Moderate), mode of inheritance: AR
• mitochondrial DNA deletion syndrome with progressive myopathy (Moderate), mode of inheritance: AD
• mitochondrial DNA deletion syndrome with progressive myopathy (Supportive), mode of inheritance: AD
• mitochondrial DNA deletion syndrome with progressive myopathy (Strong), mode of inheritance: AD
• Seckel syndrome 8 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Progressive external ophthalmoplegia with mitochondrial deletions, autosomal dominant, 6; Seckel syndrome 8; Rothmund-Thomson syndrome, type 4	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; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic	23352259; 24389050; 37055165

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DNA2 gene.

• ROTHMUND-THOMSON SYNDROME, TYPE 4 (4 variants)
• Rothmund-Thomson syndrome (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DNA2 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			5	107	7	119
missense		3	322	13	4	342
nonsense			11			11
start loss						0
frameshift		5	22		1	28
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1	11	1		13
splice region		1	12	20	3	36
non coding	1		6	114	63	184
Total	1	9	378	235	75

Variants in DNA2

This is a list of pathogenic ClinVar variants found in the DNA2 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-68414836-TA-T			Likely benign (Jul 31, 2018)
10-68414950-T-A			Benign (Jun 23, 2018)
10-68415060-CA-C			Uncertain significance (Mar 04, 2022)
10-68415065-T-C			Uncertain significance (Oct 21, 2021)
10-68415085-T-C			Uncertain significance (Sep 23, 2023)
10-68415100-T-C			Uncertain significance (Feb 14, 2022)
10-68415105-G-T			Likely benign (Nov 05, 2023)
10-68415126-G-A			Likely benign (Dec 03, 2022)
10-68415128-A-G			Benign (Jun 26, 2018)
10-68415205-CA-C			Benign (Aug 20, 2019)
10-68415275-CT-C			Benign (Aug 12, 2019)
10-68416402-G-A			Benign (Jun 14, 2018)
10-68416697-G-T			Likely benign (Jun 03, 2023)
10-68416697-G-GA			Benign (Jan 15, 2022)
10-68416702-AG-A		Seckel syndrome 8 • Ateleiotic dwarfism	Pathogenic/Likely pathogenic (Feb 01, 2014)
10-68416712-T-C			Likely benign (May 11, 2022)
10-68416724-T-C			Likely benign (Nov 01, 2022)
10-68416727-A-G			Likely benign (Nov 01, 2022)
10-68416732-T-C			Uncertain significance (Jun 22, 2022)
10-68416736-C-G			Likely benign (Oct 01, 2022)
10-68416736-C-T		not specified	Likely benign (May 19, 2017)
10-68416739-C-A			Uncertain significance (Nov 07, 2019)
10-68416749-G-A			Uncertain significance (Nov 28, 2023)
10-68416753-G-A			Uncertain significance (Jul 06, 2022)
10-68416755-T-G			Uncertain significance (Feb 28, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DNA2	protein_coding	protein_coding	ENST00000399180	21	58059

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.27e-18	0.652	124216	4	433	124653	0.00175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.736	524	574	0.914	0.0000285	7492
Missense in Polyphen		139	178.81	0.77736		2334
Synonymous	0.466	193	201	0.958	0.00000981	2124
Loss of Function	1.98	36	51.3	0.702	0.00000254	688

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000862	0.000861
Ashkenazi Jewish	0.000123	0.0000993
East Asian	0.000470	0.000445
Finnish	0.00122	0.00111
European (Non-Finnish)	0.000356	0.000345
Middle Eastern	0.000470	0.000445
South Asian	0.0119	0.0111
Other	0.000886	0.000826

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key enzyme involved in DNA replication and DNA repair in nucleus and mitochondrion. Involved in Okazaki fragments processing by cleaving long flaps that escape FEN1: flaps that are longer than 27 nucleotides are coated by replication protein A complex (RPA), leading to recruit DNA2 which cleaves the flap until it is too short to bind RPA and becomes a substrate for FEN1. Also involved in 5'-end resection of DNA during double- strand break (DSB) repair: recruited by BLM and mediates the cleavage of 5'-ssDNA, while the 3'-ssDNA cleavage is prevented by the presence of RPA. Also involved in DNA replication checkpoint independently of Okazaki fragments processing. Possesses different enzymatic activities, such as single-stranded DNA (ssDNA)- dependent ATPase, 5'-3' helicase and endonuclease activities. While the ATPase and endonuclease activities are well-defined and play a key role in Okazaki fragments processing and DSB repair, the 5'-3' DNA helicase activity is subject to debate. According to various reports, the helicase activity is weak and its function remains largely unclear. Helicase activity may promote the motion of DNA2 on the flap, helping the nuclease function. {ECO:0000269|PubMed:16595799, ECO:0000269|PubMed:16595800, ECO:0000269|PubMed:18995831, ECO:0000269|PubMed:19487465, ECO:0000269|PubMed:21325134, ECO:0000269|PubMed:21572043, ECO:0000269|PubMed:22570407, ECO:0000269|PubMed:22570476}.
• Disease: DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 6 (PEOA6) [MIM:615156]: A disorder characterized by muscle weakness, mainly affecting the lower limbs, external ophthalmoplegia, exercise intolerance, and mitochondrial DNA deletions on muscle biopsy. Symptoms may appear in childhood or adulthood and show slow progression. {ECO:0000269|PubMed:23352259}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Seckel syndrome 8 (SCKL8) [MIM:615807]: A rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and mental retardation. {ECO:0000269|PubMed:24389050}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: DNA replication - Homo sapiens (human);HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);DNA Repair;Gene expression (Transcription);DNA Double-Strand Break Repair;Generic Transcription Pathway;Homology Directed Repair;RNA Polymerase II Transcription;G2/M DNA damage checkpoint;G2/M Checkpoints;Cell Cycle Checkpoints;DNA Replication;Removal of the Flap Intermediate;Processive synthesis on the lagging strand;Lagging Strand Synthesis;DNA strand elongation;Synthesis of DNA;S Phase;Removal of the Flap Intermediate from the C-strand;Processive synthesis on the C-strand of the telomere;Telomere C-strand (Lagging Strand) Synthesis;Extension of Telomeres;Telomere Maintenance;Chromosome Maintenance;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Cell Cycle;Cell Cycle, Mitotic;Processing of DNA double-strand break ends;Presynaptic phase of homologous DNA pairing and strand exchange;Homologous DNA Pairing and Strand Exchange;Resolution of D-loop Structures through Holliday Junction Intermediates;Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA);Resolution of D-Loop Structures;HDR through Homologous Recombination (HRR) (Consensus)

Haploinsufficiency Scores

• pHI: 0.622
• hipred: Y
• hipred_score: 0.704
• ghis: 0.606

Essentials

• essential_gene_CRISPR2: E
• gene_indispensability_pred: N
• gene_indispensability_score: 0.381

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dna2
• 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); neoplasm; cellular phenotype

Gene ontology

• Biological process: DNA replication checkpoint;telomere maintenance;DNA double-strand break processing;DNA replication;mitochondrial DNA replication;base-excision repair;telomere maintenance via semi-conservative replication;DNA duplex unwinding;DNA replication, Okazaki fragment processing;DNA replication, removal of RNA primer;mitochondrial DNA repair;G-quadruplex DNA unwinding;positive regulation of DNA replication;replication fork reversal;nucleic acid phosphodiester bond hydrolysis;t-circle formation;mitotic telomere maintenance via semi-conservative replication
• Cellular component: nuclear chromosome, telomeric region;nucleus;nucleoplasm;cytoplasm;mitochondrion;gamma DNA polymerase complex;mitochondrial nucleoid
• Molecular function: DNA binding;DNA helicase activity;RNA binding;helicase activity;nuclease activity;protein binding;ATP binding;ATPase activity;site-specific endodeoxyribonuclease activity, specific for altered base;5'-flap endonuclease activity;5'-3' DNA helicase activity;single-stranded DNA-dependent ATPase activity;metal ion binding;4 iron, 4 sulfur cluster binding