SCN4B
protein-codingsodium voltage-gated channel beta subunit 4, the group of Sodium voltage-gated channel beta subunits|V-set domain containing
Gene summary
The protein encoded by this gene is one of several sodium channel beta subunits. These subunits interact with voltage-gated alpha subunits to change sodium channel kinetics. The encoded transmembrane protein forms interchain disulfide bonds with SCN2A. Defects in this gene are a cause of long QT syndrome type 10 (LQT10). Three protein-coding and one non-coding transcript variant have been found for this gene.[provided by RefSeq, Mar 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~19.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0012737
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0018054
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012737
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: ClinGen
SCN4B encodes for a beta subunit of the cardiac sodium channel. Its association with LQTS is based on a study utilizing a candidate gene approach which identified a missense variant in a genotype-negative LQTS family but not in other genotype-negative LQTS patients. Because of the candidate gene approach, lack of segregation or case-control data and paucity of additional genetic and experimental data, this gene-disease association was classified as disputed. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
Inheritance Pattern: Unknown
Disease ID:MONDO:0012737
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: In Atrial fibrillation and Long QT syndrome, surveillance and medical and/or surgical management related to arrhythmias may be helpful to help decrease morbidity
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SCN4B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_174934.4. 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 | 3 | 68 | 71 | |||
| missense | 2 | 130 | 18 | 150 | ||
| nonsense | 4 | 4 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 6 | 1 | 7 | |||
| splice donor/acceptor (+/-2bp) | 7 | 7 | ||||
| Total | 2 | 0 | 151 | 86 | 1 | 240 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_777594.1 | 5 | MANE Select | |
| Ensembl | ENSP00000322460.4 | 5 | MANE Select | |
| RefSeq | NP_001135820.1 | 3 | Standard | |
| RefSeq | NP_001135821.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
- Antiarrhythmic Pathway, Pharmacodynamics
- Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways
- Developmental Biology
- Phase 0 - rapid depolarisation
Biological Process
- sodium ion transport
- positive regulation of sodium ion transport
- sodium ion transmembrane transport
- cardiac muscle contraction
- regulation of ventricular cardiac muscle cell membrane repolarization
Molecular Function
- voltage-gated ion channel activity
- voltage-gated sodium channel activity
- sodium channel regulator activity
- ion channel binding
- voltage-gated sodium channel activity involved in cardiac muscle cell action potential
Cellular Component
- voltage-gated sodium channel complex
- intercalated disc
- intrinsic component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000324727
- Coding exons
- 5
- Length
- 19512
- Individuals with no LoFs
- 125720
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 28
- Defined
- 125748
- p
- 0.000111
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.182 | 136 | 130 | 1.04 | 0.00000786 | 1487 |
| Missense (PolyPhen) | 46 | 46.201 | 0.99565 | 534 | ||
| Synonymous | -0.116 | 62 | 60.9 | 1.02 | 0.00000418 | 468 |
| Loss of Function | -0.270 | 9 | 8.17 | 1.10 | 4.50e-7 | 101 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0.00050 | 0.00050 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000088 | 0.000088 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Modulates channel gating kinetics. Causes negative shifts in the voltage dependence of activation of certain alpha sodium channels, but does not affect the voltage dependence of inactivation. Modulates the susceptibility of the sodium channel to inhibition by toxic peptides from spider, scorpion, wasp and sea anemone venom. {ECO:0000269|PubMed:24297919}.;
- Disease
- DISEASE: Long QT syndrome 10 (LQT10) [MIM:611819]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. {ECO:0000269|PubMed:17592081}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrial fibrillation, familial, 17 (ATFB17) [MIM:611819]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:23604097}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.127
Intolerance Scores
- LoFtool
- 0.363
- RVIS EVS
- -0.38
- RVIS percentile EVS
- 27.42
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.436
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |