DNA2

Chr 10ADAR

DNA replication helicase/nuclease 2

Also known as: DNA2L, RTS4, hDNA2

NCBI Gene: 1763 ENSG00000138346 OMIM: 601810

The protein functions as a conserved helicase/nuclease that maintains mitochondrial and nuclear DNA stability. Mutations cause autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOA6) and autosomal recessive conditions including Seckel syndrome 8 and Rothmund-Thomson syndrome type 4. The pathogenic mechanism involves impaired DNA maintenance leading to mitochondrial DNA instability in the dominant form and broader DNA repair defects in the recessive disorders.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the DNA2/NAM7 helicase family. The encoded protein is a conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability. Mutations in this gene are associated with autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) and Seckel syndrome 8. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.933 OMIM phenotypes

Clinical Summary— DNA2

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

19 unique Pathogenic / Likely Pathogenic· 552 VUS of 1041 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 1.97

OE 0.70 (0.54–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.74Z-score

OE missense 0.91 (0.85–0.98)

524 obs / 573.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.54–0.93)

0≤0.351.4

Missense OE?0.91 (0.85–0.98)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 36 / 51.3Missense obs/exp: 524 / 573.6Syn Z: 0.47

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedDNA2-related microcephalic primordial dwarfism with or without poikiloderma and cataractsOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6455th %ile

GOF

0.5072th %ile

LOF

0.3454th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

LOFWe hypothesize that haploinsufficiency for the DNA2 protein due to truncating mutations results in mitochondrial genome instability and clinical symptoms of early-onset myopathy.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 28554558 ↗

ClinVar Variant Classifications

1041 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic14

VUS552

Likely Benign342

Benign80

Conflicting26

Pathogenic

Likely Pathogenic

552

VUS

342

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	2	0	5
Likely Pathogenic	8	3	3	0	14
VUS	51	451	39	11	552
Likely Benign	1	12	164	165	342
Benign	0	3	70	7	80
Conflicting	—				26
Total	62	470	278	183	1,019

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap DNA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →