SPTBN2

Chr 11

spectrin beta, non-erythrocytic 2

Also known as: GTRAP41, SCA5, SCAR14

NCBI Gene: 6712 ENSG00000173898 UniProt: O15020

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Spectrins are principle components of a cell's membrane-cytoskeleton and are composed of two alpha and two beta spectrin subunits. The protein encoded by this gene (SPTBN2), is called spectrin beta non-erythrocytic 2 or beta-III spectrin. It is related to, but distinct from, the beta-II spectrin gene which is also known as spectrin beta non-erythrocytic 1 (SPTBN1). SPTBN2 regulates the glutamate signaling pathway by stabilizing the glutamate transporter EAAT4 at the surface of the plasma membrane. Mutations in this gene cause a form of spinocerebellar ataxia, SCA5, that is characterized by neurodegeneration, progressive locomotor incoordination, dysarthria, and uncoordinated eye movements. [provided by RefSeq, Dec 2009]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.36

Clinical Summary— SPTBN2

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Gene-Disease Validity (ClinGen)

spinocerebellar ataxia type 5 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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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ClinVar Variants

59 unique Pathogenic / Likely Pathogenic· 663 VUS of 1406 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SPTBN2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.27 (0.20–0.36)

0≤0.351.4

Missense OE?0.81 (0.77–0.85)

0≤0.61.4

Synonymous OE?1.03

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

This gene — mechanism propensity

0.7325th %ile

GOF

0.79top 10%

LOF

0.2583th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-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

LOF47% of P/LP variants are LoF · LOEUF 0.36

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 char1

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

References

1.PMID 31617442 ↗

ClinVar Variant Classifications

1406 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25

Likely Pathogenic34

VUS663

Likely Benign430

Benign64

Conflicting155

Pathogenic

Likely Pathogenic

663

VUS

430

Likely Benign

Benign

155

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	5	1	0	25
Likely Pathogenic	9	24	1	0	34
VUS	5	604	40	14	663
Likely Benign	0	58	102	270	430
Benign	0	8	23	33	64
Conflicting	—				155
Total	33	699	167	317	1,371

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap SPTBN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →