PLCH2

Chr 1

phospholipase C eta 2

Also known as: PLC-L4, PLC-eta2, PLCL4, PLCeta2

NCBI Gene: 9651 ENSG00000149527 UniProt: O75038 OMIM: 612836

Phospholipase C eta 2 cleaves PtdIns(4,5)P2 to generate the second messengers diacylglycerol and inositol 1,4,5-trisphosphate, and may be important for formation and maintenance of neuronal networks in the postnatal brain. Mutations cause neurodevelopmental disorders with autosomal recessive inheritance. The gene shows no constraint against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

PLCH2 is a member of the PLC-eta family of the phosphoinositide-specific phospholipase C (PLC) superfamily of enzymes that cleave PtdIns(4,5) P2 to generate second messengers inositol 1,4,5-trisphosphate and diacylglycerol (Zhou et al., 2005 [PubMed 16107206]).[supplied by OMIM, Jun 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.96

Clinical Summary— PLCH2

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.96LOEUF

pLI 0.000

Z-score 1.80

OE 0.72 (0.55–0.96)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.23Z-score

OE missense 0.87 (0.81–0.93)

615 obs / 707.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.55–0.96)

0≤0.351.4

Missense OE?0.87 (0.81–0.93)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 35 / 48.6Missense obs/exp: 615 / 707.3Syn Z: -1.50

This gene — mechanism propensity

0.6746th %ile

GOF

0.72top 25%

LOF

0.4430th %ile

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

GOFprediction above median

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.