SPTBN1

Chr 2AD

spectrin beta, non-erythrocytic 1

Also known as: DDISBA, ELF, HEL102, SPTB2, betaSpII

NCBI Gene: 6711 ENSG00000115306 UniProt: Q01082 OMIM: 182790

Spectrin beta chain, non-erythrocytic 1 is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton and plays a critical role in central nervous system development and function. Mutations cause autosomal dominant developmental delay with impaired speech and behavioral abnormalities. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0), indicating that even single pathogenic variants can cause disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein contains an N-terminal actin-binding domain, and 17 spectrin repeats which are involved in dimer formation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.091 OMIM phenotype

Clinical Summary— SPTBN1

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Gene-Disease Validity (ClinGen)

developmental delay, impaired speech, and behavioral abnormalities · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

65 unique Pathogenic / Likely Pathogenic· 504 VUS of 722 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 9.70

OE 0.04 (0.02–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.54Z-score

OE missense 0.66 (0.62–0.70)

931 obs / 1411.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.02–0.09)

0≤0.351.4

Missense OE?0.66 (0.62–0.70)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 5 / 119.4Missense obs/exp: 931 / 1411.2Syn Z: -3.44

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPTBN1-related developmental disorderLOFAD

This gene — mechanism propensity

0.4785th %ile

GOF

0.6930th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function 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 loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF65% of P/LP variants are LoF · LOEUF 0.09

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.

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

ClinVar Variant Classifications

722 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24

Likely Pathogenic41

VUS504

Likely Benign87

Benign10

Conflicting5

Pathogenic

Likely Pathogenic

504

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	6	0	0	24
Likely Pathogenic	24	16	1	0	41
VUS	15	470	17	2	504
Likely Benign	0	40	4	43	87
Benign	0	1	1	8	10
Conflicting	—				5
Total	57	533	23	53	671

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap SPTBN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →