CRNKL1

Chr 20

crooked neck pre-mRNA splicing factor 1

This protein is involved in pre-mRNA splicing as a component of the minor spliceosome that processes U12-type introns. Mutations cause autosomal dominant microcephaly with progressive features, simplified gyral pattern, and cerebellar hypoplasia. The gene is highly constrained against loss-of-function variants (LOEUF 0.546), indicating that even heterozygous disruption can cause significant developmental abnormalities affecting brain structure.

ResearchSummary from RefSeq, OMIM, UniProt

Involved in pre-mRNA splicing process (PubMed:11991638, PubMed:12084575, PubMed:28076346, PubMed:28502770). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable)

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.55

Clinical Summary— CRNKL1

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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

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.000

Z-score 4.16

OE 0.37 (0.26–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.88Z-score

OE missense 0.89 (0.82–0.96)

420 obs / 473.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.26–0.55)

0≤0.351.4

Missense OE?0.89 (0.82–0.96)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 19 / 51.1Missense obs/exp: 420 / 473.9Syn Z: -0.80

This gene — mechanism propensity

0.76top 25%

GOF

0.72top 25%

LOF

0.3065th %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.