HELZ2

Chr 20

helicase with zinc finger 2

Also known as: PDIP-1, PRIC285

NCBI Gene: 85441 ENSG00000130589 UniProt: Q9BYK8

The protein functions as an ATP-dependent RNA helicase with 3' to 5' exoribonuclease activity that degrades highly structured RNAs, and serves as a transcriptional coactivator for nuclear receptors including peroxisome proliferator-activated receptors. Mutations cause autosomal recessive neurodevelopmental disorder with early-onset seizures, developmental delay, and intellectual disability. The gene is highly constrained against loss-of-function mutations, indicating intolerance to haploinsufficiency.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a nuclear transcriptional co-activator for peroxisome proliferator activated receptor alpha. The encoded protein contains a zinc finger and is a helicase that appears to be part of the peroxisome proliferator activated receptor alpha interacting complex. This gene is a member of the DNA2/NAM7 helicase gene family. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.47

Clinical Summary— HELZ2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

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ClinVar Variants

549 VUS of 676 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.000

Z-score 5.75

OE 0.35 (0.26–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.43Z-score

OE missense 0.97 (0.93–1.01)

1684 obs / 1734.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.26–0.47)

0≤0.351.4

Missense OE?0.97 (0.93–1.01)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 31 / 89.8Missense obs/exp: 1684 / 1734.7Syn Z: -0.58

This gene — mechanism propensity

0.6161th %ile

GOF

0.6150th %ile

LOF

0.2969th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

676 submitted variants in ClinVar

ClinVar

Classification Summary

VUS549

Likely Benign71

Benign6

Conflicting1

549

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	549	0	0	549
Likely Benign	0	57	0	14	71
Benign	0	3	0	3	6
Conflicting	—				1
Total	0	609	0	17	627

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 82) ClinVar copy-number / structural variants overlap HELZ2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →