SPTBN2

Chr 11ADAR

spectrin beta, non-erythrocytic 2

Also known as: GTRAP41, SCA5, SCAR14

NCBI Gene: 6712 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.

GeneReviews OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spinocerebellar ataxia 5MIM #600224

Spinocerebellar ataxia, autosomal recessive 14MIM #615386

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

The dominant disease is caused by dominant-negative changes and the recessive disease by loss of function (Gene2Phenotype). A single heterozygous truncating variant therefore fits the recessive disease and does not by itself explain a dominant presentation; a novel missense has to be read against the dominant mechanism.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.36

LOEUF

Multiple*

Mechanism· G2P

📖

GeneReview available — SPTBN2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in SPTBN2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 21

2,819 rare PASS variants

Rare truncating (LoF)

1 in 710

237 rare PASS variants

Rare synonymous (reference)

1 in 25

1,417 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPTBN2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 27	1 in 1,100
South Asian	~43k	1 in 19	1 in 300
Remaining (unassigned)	~30k	1 in 17	1 in 1,000
European (Finnish)	~27k	1 in 40	1 in 800
Admixed American	~22k	1 in 17	1 in 2,000
African / African American	~21k	1 in 18	1 in 840
East Asian	~20k	1 in 23	1 in 390
Ashkenazi Jewish	~13k	1 in 56	1 in 1,800
Middle Eastern	~2,884	1 in 21	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.