SPTBN1

protein-coding

spectrin beta, non-erythrocytic 1, the group of Pleckstrin homology domain containing|Spectrins

Gene summary

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]

MANE transcript

NM_003128.3

Inheritance

ClinVar variants

P:82U:580B:129

Top phenotype

Devlopmental delay, impaired speech, and behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr2:54,456,327-54,671,446

External References & Databases

Ensembl (ENSG00000115306)

Transcript & Mutation Effects

hg38 • Region Span ~215.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay, impaired speech, and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859178

Submitter: Labcorp Genetics (formerly Invitae)

developmental delay, impaired speech, and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859178

Submitter: G2P

developmental delay, impaired speech, and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859178

Submitter: PanelApp Australia

developmental delay, impaired speech, and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859178

Submitter: ClinGen

The *SPTBN1* gene is located on chromosome 2 at 2p16.2 and encodes neuronal beta-II spectrin, which forms tetramers with alpha-II spectrin that intercalate F-actin rings to build a submembranous periodic skeleton. *SPTBN1* was first reported in relation to autosomal dominant developmental delay, impaired speech, and behavioral abnormalities in 2021 (Cousin et al., PMID: 34211179). 16 variants (9 missense, 5 nonsense, 1 frameshift, and 1 intronic splice altering) that have been reported in 16 probands in four publications (PMIDs: 34211179, 33847457, 40869952, 39162370) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence experimental evidence (12 pts.) has been reached. Loss-of-function is a mechanism of disease, although the mechanism of pathogenicity for missense variants is still unclear. This gene-disease relationship is also supported by animal models and protein-protein interactions (PMIDs: 12543979, 31209033). In summary, there is definitive evidence to support the relationship between *SPTBN1* and autosomal dominant developmental delay, impaired speech, and behavioral abnormalities. This gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders GCEP on 10/15/2023. It was re-evaluated on 3/25/2026. As a result of this reevaluation, the classification increased from Strong to Definitive with the addition of multiple case reports (PMID: 40869952, 39162370, SOP Version 12).

Clinical Genomic Database (CGD)

Devlopmental delay, impaired speech, and behavioral abnormalitiesAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 34211179

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPTBN1 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 334

Inborn genetic diseasesTotal: 237

Developmental delay, impaired speech, and behavioral abnormalitiesTotal: 148

SPTBN1-related disorderTotal: 79

not specifiedTotal: 71

Neurodevelopmental disorderTotal: 5

See casesTotal: 3

Developmental delay, impaired speech, and behavioral abnormalities, with or without seizuresTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003128.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	75 clinvar	6 clinvar	85
missense	5 clinvar	18 clinvar	548 clinvar	46 clinvar	1 clinvar	618
nonsense	8 clinvar	18 clinvar	6 clinvar	1 clinvar		33
start loss						0
frameshift	12 clinvar	8 clinvar	6 clinvar			26
splice donor/acceptor (+/-2bp)	2 clinvar	11 clinvar	16 clinvar			29
Total	27	55	580	122	7	791

Highest pathogenic variant AF is 0.0000013737038

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003128.3	RefSeq	NP_003119.2	35	MANE Select
ENST00000356805.9	Ensembl	ENSP00000349259.4	35	MANE Select
NM_178313.3	RefSeq	NP_842565.2	31	Standard
ENST00000333896.5	Ensembl	ENSP00000334156.5	31	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TGF-beta Signaling Pathway
Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways
Developmental Biology
Signal Transduction
Vesicle-mediated transport

Biological Process

MAPK cascade
mitotic cytokinesis
endoplasmic reticulum to Golgi vesicle-mediated transport
plasma membrane organization
cytoskeleton organization

Molecular Function

RNA binding
actin binding
Ras guanyl-nucleotide exchange factor activity
structural constituent of cytoskeleton
protein binding

Cellular Component

nucleolus
cytoplasm
cytosol
spectrin
postsynaptic density

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356805
Coding exons: 35
Length: 213391
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.54	931	1.41e+3	0.660	0.0000895	15788
Missense (PolyPhen)		224	521.25	0.42974		5848
Synonymous	-3.44	671	567	1.18	0.0000389	4329
Loss of Function	9.70	5	119	0.0419	0.00000605	1332

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.;

Recessive Scores

pRec: 0.371

Intolerance Scores

LoFtool: 0.131
RVIS EVS: -3.86
RVIS percentile EVS: 0.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.905

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium