CCBE1

Chr 18AR

collagen and calcium binding EGF domains 1

Also known as: HKLLS1

NCBI Gene: 147372 ENSG00000183287 UniProt: Q6UXH8 OMIM: 612753

The protein is required for lymphangioblast budding and angiogenic sprouting from venous endothelium during embryonic development. Mutations cause Hennekam lymphangiectasia-lymphedema syndrome 1, a generalized lymphatic dysplasia with autosomal recessive inheritance. This gene shows minimal constraint against loss-of-function variants (pLI near zero), which is consistent with its recessive disease pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is thought to function in extracellular matrix remodeling and migration. It is predominantly expressed in the ovary, but down regulated in ovarian cancer cell lines and primary carcinomas, suggesting its role as a tumour suppressor. Mutations in this gene have been associated with Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymphatic dysplasia in humans. [provided by RefSeq, Mar 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.011 OMIM phenotype

Clinical Summary— CCBE1

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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

18 unique Pathogenic / Likely Pathogenic· 259 VUS of 566 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?

1.01LOEUF

pLI 0.000

Z-score 1.54

OE 0.64 (0.42–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.69Z-score

OE missense 1.13 (1.02–1.25)

265 obs / 235.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.64 (0.42–1.01)

0≤0.351.4

Missense OE?1.13 (1.02–1.25)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 14 / 21.8Missense obs/exp: 265 / 235.2Syn Z: -0.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCCBE1-related Hennekam lymphangiectasia-lymphedema syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.74top 25%

GOF

0.5954th %ile

LOF

0.3744th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

566 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic5

VUS259

Likely Benign182

Benign75

Conflicting27

Pathogenic

Likely Pathogenic

259

VUS

182

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	4	1	0	13
Likely Pathogenic	4	1	0	0	5
VUS	3	156	97	3	259
Likely Benign	0	4	86	92	182
Benign	0	2	71	2	75
Conflicting	—				27
Total	15	167	255	97	561

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

View in ClinVar →

75 pathogenic / likely-pathogenic (of 85) ClinVar copy-number / structural variants overlap CCBE1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →