DKC1

Chr XXLDXLR

dyskerin pseudouridine synthase 1

Also known as: CBF5, CHINE1, DKC, DKCX, NAP57, NOLA4, XAP101

NCBI Gene: 1736 ENSG00000130826 UniProt: O60832

This gene functions in two distinct complexes. It plays an active role in telomerase stabilization and maintenance, as well as recognition of snoRNAs containing H/ACA sequences which provides stability during biogenesis and assembly into H/ACA small nucleolar RNA ribonucleoproteins (snoRNPs). This gene is highly conserved and widely expressed, and may play additional roles in nucleo-cytoplasmic shuttling, DNA damage response, and cell adhesion. Mutations have been associated with X-linked dyskeratosis congenita. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Primary Disease Associations & Inheritance

?Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 1MIM #301108

XLD

Dyskeratosis congenita, X-linkedMIM #305000

XLR

UniProtHoyeraal-Hreidarsson syndrome

290

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— DKC1

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Gene-Disease Validity (ClinGen)

DKC1-related disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

26 Pathogenic / Likely Pathogenic· 83 VUS of 290 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

Dual constrained — LoF & missense intolerant

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.

0.19LOEUF

pLI 0.999

Z-score 4.44

OE 0.04 (0.01–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% 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.

3.40Z-score

OE missense 0.33 (0.27–0.41)

68 obs / 205.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

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.0.04 (0.01–0.19)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.33 (0.27–0.41)

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.1.08

0≤1.21.6

LoF obs/exp: 1 / 24.9Missense obs/exp: 68 / 205.0Syn Z: -0.57