GLIS2

Chr 16AR

GLIS family zinc finger 2

Also known as: NKL, NPHP7

NCBI Gene: 84662 ENSG00000126603 UniProt: Q9BZE0

This gene is a member of the GLI-similar zinc finger protein family and encodes a nuclear transcription factor with five C2H2-type zinc finger domains. The protein encoded by this gene is widely expressed at low levels in the neural tube and peripheral nervous system and likely promotes neuronal differentiation. It is abundantly expressed in the kidney and may have a role in the regulation of kidney morphogenesis. p120 regulates the expression level of this protein and induces the cleavage of this protein's C-terminal zinc finger domain. This protein also promotes the nuclear translocation of p120. Mutations in this gene cause nephronophthisis (NPHP), an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial lymphohistiocytic cell infiltration, and development of cysts at the corticomedullary border of the kidneys.[provided by RefSeq, Jan 2010]

Primary Disease Associations & Inheritance

Nephronophthisis 7MIM #611498

292

ClinVar variants

Pathogenic / LP

0.86

pLI score

Active trials

Clinical Summary— GLIS2

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Gene-Disease Validity (ClinGen)

nephronophthisis 7 · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.86) — some intolerance to loss-of-function variants.

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ClinVar Variants

20 Pathogenic / Likely Pathogenic· 185 VUS of 292 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.41LOEUF

pLI 0.858

Z-score 3.14

OE 0.13 (0.05–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.79Z-score

OE missense 0.88 (0.80–0.97)

290 obs / 330.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.05–0.41)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.80–0.97)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10

0≤1.21.6

LoF obs/exp: 2 / 15.2Missense obs/exp: 290 / 330.5Syn Z: -0.94