SPTBN2

Chr 11ADAR

spectrin beta, non-erythrocytic 2

ENSG00000173898 UniProt: O15020 OMIM: 604985

The protein stabilizes the glutamate transporter EAAT4 at the plasma membrane and serves as a key component of the neuronal membrane cytoskeleton. Mutations cause spinocerebellar ataxia 5 (SCA5) and spinocerebellar ataxia autosomal recessive 14 (SCAR14), both characterized by progressive cerebellar degeneration with ataxia, dysarthria, and oculomotor dysfunction. The gene shows both autosomal dominant and autosomal recessive inheritance patterns with a predicted gain-of-function mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismAD/ARLOEUF 0.362 OMIM phenotypes

Clinical Summary— SPTBN2

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Gene-Disease Validity (ClinGen)

spinocerebellar ataxia type 5 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.36LOEUF

pLI 0.000

Z-score 7.64

OE 0.27 (0.20–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

2.63Z-score

OE missense 0.81 (0.77–0.85)

1209 obs / 1495.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.27 (0.20–0.36)

0≤0.351.4

Missense OE0.81 (0.77–0.85)

0≤0.61.4

Synonymous OE1.03

0≤1.21.6

LoF obs/exp: 34 / 126.8Missense obs/exp: 1209 / 1495.8Syn Z: -0.59

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSPTBN2-related infantile ataxia with oculomotor and pyramidal signsDNAD

definitiveSPTBN2-related spinocerebellar ataxiaLOFAR

0.7325th %ile

GOF

0.79top 10%

LOF

0.2583th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNAccordingly, 2 major phenotypes have been linked to SPTBN2: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder charPMID:31617442

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