ZSCAN2

Chr 15

zinc finger and SCAN domain containing 2

Also known as: ZFP29, ZNF854

NCBI Gene: 54993 ENSG00000176371 UniProt: Q7Z7L9

ZSCAN2 encodes a zinc finger transcription factor that regulates gene expression during spermatogenesis, particularly in post-meiotic stages of sperm development. Mutations cause autosomal recessive intellectual disability with developmental delay. The gene is highly constrained against loss-of-function variants (pLI essentially 0), indicating that complete loss of function is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene contains several copies of zinc finger motif, which is commonly found in transcriptional regulatory proteins. Studies in mice show that this gene is expressed during embryonic development, and specifically in the testis in adult mice, suggesting that it may play a role in regulating genes in germ cells. Alternative splicing of this gene results in several transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.80

Clinical Summary— ZSCAN2

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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

100 VUS of 111 total submissions

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?

0.80LOEUF

pLI 0.000

Z-score 2.28

OE 0.48 (0.30–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.10Z-score

OE missense 1.02 (0.93–1.11)

361 obs / 355.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.48 (0.30–0.80)

0≤0.351.4

Missense OE?1.02 (0.93–1.11)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 11 / 22.7Missense obs/exp: 361 / 355.6Syn Z: -1.84

This gene — mechanism propensity

0.78top 25%

GOF

0.72top 25%

LOF

0.3162th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

111 submitted variants in ClinVar

ClinVar

Classification Summary

VUS100

Likely Benign6

Benign1

100

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	0	100	0	100
Likely Benign	0	5	1	6
Benign	1	0	0	1
Total	1	105	1	107

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 59) ClinVar copy-number / structural variants overlap ZSCAN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →