BICD2

Chr 9AD

BICD cargo adaptor 2

Also known as: SMALED2, SMALED2A, SMALED2B, bA526D8.1

NCBI Gene: 23299 ENSG00000185963 UniProt: Q8TD16 OMIM: 609797

The protein mediates dynein-mediated transport along microtubules toward the minus end and functions at the Golgi apparatus. Loss-of-function mutations cause autosomal dominant spinal muscular atrophy, lower extremity-predominant types 2A and 2B. The high pLI score (0.98) indicates this gene is highly intolerant to loss-of-function variants, consistent with the dominant inheritance pattern where haploinsufficiency drives pathogenicity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is one of two human homologs of Drosophila bicaudal-D and a member of the Bicoid family. It has been implicated in dynein-mediated, minus end-directed motility along microtubules. It has also been reported to be a phosphorylation target of NIMA related kinase 8. Two alternative splice variants have been described. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.302 OMIM phenotypes

Clinical Summary— BICD2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.983

Z-score 4.40

OE 0.13 (0.07–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.20Z-score

OE missense 0.74 (0.68–0.80)

414 obs / 561.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.30)

0≤0.351.4

Missense OE?0.74 (0.68–0.80)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 4 / 30.0Missense obs/exp: 414 / 561.0Syn Z: -0.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveBICD2-related proximal spinal muscular atrophy with brain anomaliesOTHERAD

This gene — mechanism propensity

0.5771th %ile

GOF

0.4874th %ile

LOF

0.66top 25%

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

LOFprediction above median · LOEUF 0.30

GOF1 literature citation

Literature Evidence

GOFHere, using biochemical and single-molecule motility assays, we demonstrate that BICD2 disease mutations cause a gain of function in the motility of DDB complexes both in vitro and in cells.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References