DNA2

Chr 10ADAR

DNA replication helicase/nuclease 2

Also known as: DNA2L, RTS4, hDNA2

NCBI Gene: 1763ENSG00000138346UniProt: P51530

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]

Primary Disease Associations & Inheritance

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 6MIM #615156
AD
Rothmund-Thomson syndrome, type 4MIM #620819
AR
Seckel syndrome 8MIM #615807
AR
1
Active trials
15
Pathogenic / LP
381
ClinVar variants
49
Pubs (1 yr)
0.7
Missense Z
0.93
LOEUF
Clinical Summary— DNA2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
15 Pathogenic / Likely Pathogenic· 233 VUS of 381 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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 OE0.70 (0.54–0.93)
0≤0.351.4
Missense OE0.91 (0.85–0.98)
0≤0.61.4
Synonymous OE0.96
0≤1.21.6
LoF obs/exp: 36 / 51.3Missense obs/exp: 524 / 573.6Syn Z: 0.47
LOFDN
DN
0.6455th %ile
GOF
0.5072th %ile
LOF
0.3454th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 27% of P/LP variants are LoF
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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.PMID:28554558

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

ClinVar Variant Classifications

381 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic3
VUS233
Likely Benign124
Benign4
Conflicting5
12
Pathogenic
3
Likely Pathogenic
233
VUS
124
Likely Benign
4
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
9
0
12
Likely Pathogenic
2
1
0
0
3
VUS
16
181
32
4
233
Likely Benign
0
3
55
66
124
Benign
0
0
4
0
4
Conflicting
—5
Total2018610070381

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

View in ClinVar →

DNA2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

DNA2-related microcephalic primordial dwarfism with or without poikiloderma and cataracts

limited
ARUndeterminedAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗
frameshift variantmissense variantintron variantinframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients