INS
protein-codinginsulin, the group of Neuropeptides
Gene summary
This gene encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified, including insulin-dependent diabetes mellitus, permanent neonatal diabetes diabetes mellitus, maturity-onset diabetes of the young type 10 and hyperproinsulinemia. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. [provided by RefSeq, May 2020]
- IDDM2
- IDDM1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007454
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0030089
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0030089
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013240
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0030089
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030089
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013240
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030089
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0030089
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0018911
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100164
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100164
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0020525
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0020525
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013240
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014535
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0015967
Submitter: ClinGen
INS and autosomal recessive monogenic diabetes INS was first reported in relation to autosomal recessive monogenic diabetes in 2010. The phenotype is usually permanent neonatal diabetes with intrauterine growth retardation requiring insulin treatment, but some individuals who are homozygous or compound heterozygous for INS regulatory variants were reported to have transient neonatal diabetes (diagnosed in early infancy but diabetes was in clinical remission at the time of publication after limited follow-up period) or diabetes diagnosed outside the neonatal period rather than permanent neonatal diabetes (Garin et al., PMID:20133622). At least 11 unique variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 16 points. Variants in this gene have been reported in at least 12 probands in 6 publications (PMIDS: 31441606, 26101329, 27487489, 25755231, 23245869, 20133622). The mechanism for disease is expected to be loss of function. This gene-disease association is supported by expression studies, animal models, and cell culture models. In summary, INS is definitively associated with autosomal recessive permanent neonatal diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting working group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability underlying the disease entities associated with INS. Therefore, we have split curations for these disease entities. The present curation refers to the entity of autosomal recessive permanent neonatal diabetes (MIM: 606176) with some rare transient neonatal of older onset cases. Other entities being curated separately include (1) autosomal dominant monogenic diabetes, which comprises OMIM entries autosomal dominant neonatal diabetes (MIM: 606176) and maturity-onset diabetes of the young 10 (MODY10; MIM:613370) and (2) hyperproinsulinemia (MIM: 616214). Type 1 diabetes (polygenic; MIM: 125852) will not be curated at this time since the contribution of INS is in the form of common variants with a small effect.
Inheritance Pattern: AD
Disease ID:MONDO:0014535
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0015967
Submitter: ClinGen
INS was first reported in relation to autosomal dominant monogenic diabetes in 2007 (Støy, et al., PMID: 17855560) and studies of large case series reported in 2008 indicated INS mutations as the second most common cause of permanent neonatal diabetes. While most reported cases are diagnosed with diabetes before 6 months of age, diabetes is less commonly diagnosed later in infancy or early childhood, as well as rarely in adolescence or early adulthood (PMID: 18162506, 18292540), sometimes referred to as MODY10 (MIM:613370). The mechanism for disease in the majority of cases is expected to be toxic gain of function, related to misfolding of the proinsulin molecule leading to ER stress and apoptosis (PMID: 9884331); consequently, these cases usually require and respond best to insulin treatment. Of note, a few studies have found such INS mutations in approximately 7% of patients who had been clinically diagnosed with type 1 diabetes in early childhood but were negative for pancreatic autoantibodies. A few INS variants appear to have distinct mechanisms affecting properties such as protein stability and/or binding to the insulin receptor. Patients with these variants appear more likely to be diagnosed with diabetes in adolescence or early adulthood and may respond to oral hypoglycemic agents (PMID: 18192540). Numerous variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of case-level and experimental data: 17.6 points. Variants in this gene have been reported in at least 11 probands in 7 publications (PMIDs: 17855560, 25721872, 816250, 20007936, 18192540, 19900242, 30182532, 28992123). Variants in this gene segregated with disease in 11 additional family members. A score of 11.6 was achieved for genetic data. This gene-disease association is supported by expression studies, animal models, and in vitro functional assays. In summary, INS is definitively associated with autosomal dominant monogenic diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting working group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability underlying the INS-related disease entities. Therefore, we have split curations for these disease entities. The present curation includes (1) autosomal dominant monogenic diabetes mellitus, which most often presents in infancy and is usually referred to as permanent neonatal diabetes (MIM: 606176), but may also occur in patients with antibody-negative type 1 diabetes in early childhood, or rarely in adolescence or young adulthood and may be referred to as maturity-onset diabetes of the young 10, (MODY10, MIM:613370). Other entities requiring separate curations include (2) Autosomal recessive diabetes mellitus (usually permanent neonatal; MIM: 606176) and (3) Hyperproinsulinemia (MIM: 616214). Type 1 diabetes (polygenic, MIM: 125852) will not be curated at this time since the contribution of INS is in the form of common variants with a small effect.
Inheritance Pattern: AD
Disease ID:MONDO:0007454
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: Endocrine
Rationale: Individuals may manifest in infancy with findings including intrauterine growth retardation, postnatal growth deficiency, and signs of diabetes mellitus (eg, hyperglycemia, glycosuria), as well as severe dehydration, and recognition can allow preventive measures related to potential sequelae, surveillance (eg, with blood glucose monitoring as well as surveillance for other common sequelae of diabetes mellitus affecting systems such as the renal and ophthalmogic systems); In the case of an acute diabetic crisis, rapid treatment (eg, with rehydration and IV insulin, transitioning to SQ insulin when stable) is indicated, though rapid-acting and (non-continuous) short-acting insulin preparations may result in severe hypoglycemia in young patients
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to INS variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000207.3. 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 | 19 | 1 | 20 | |||
| missense | 7 | 31 | 51 | 4 | 93 | |
| nonsense | 2 | 2 | 4 | |||
| start loss | 1 | 2 | 3 | |||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 7 | 35 | 56 | 23 | 1 | 122 |
Highest pathogenic variant AF is 0.0000074827335
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000198.1 | 2 | MANE Select | |
| Ensembl | ENSP00000370731.5 | 2 | MANE Select | |
| RefSeq | NP_001172026.1 | 2 | Standard | |
| RefSeq | NP_001172027.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ins | Danio rerio | Structure: pancreatic B cell Quality: increased area abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- mTOR signaling pathway - Homo sapiens (human)
- Regulation of lipolysis in adipocytes - Homo sapiens (human)
- Type I diabetes mellitus - Homo sapiens (human)
- Type II diabetes mellitus - Homo sapiens (human)
Biological Process
- negative regulation of acute inflammatory response
- glucose metabolic process
- regulation of transcription, DNA-templated
- regulation of cellular amino acid metabolic process
- endoplasmic reticulum to Golgi vesicle-mediated transport
Molecular Function
- protease binding
- insulin receptor binding
- insulin-like growth factor receptor binding
- hormone activity
- protein binding
Cellular Component
- Golgi membrane
- extracellular region
- extracellular space
- endoplasmic reticulum lumen
- Golgi lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000397262
- Coding exons
- 2
- Length
- 1563
- Individuals with no LoFs
- 123864
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 123865
- p
- 0.00000404
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.900 | 44 | 64.3 | 0.684 | 0.00000387 | 675 |
| Missense (PolyPhen) | 12 | 27.822 | 0.43132 | 284 | ||
| Synonymous | -0.506 | 32 | 28.6 | 1.12 | 0.00000150 | 243 |
| Loss of Function | 1.39 | 1 | 3.99 | 0.251 | 2.70e-7 | 30 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.;
- Disease
- DISEASE: Hyperproinsulinemia (HPRI) [MIM:616214]: An autosomal dominant condition characterized by elevated levels of serum proinsulin-like material. {ECO:0000269|PubMed:1601997, ECO:0000269|PubMed:2196279, ECO:0000269|PubMed:3470784, ECO:0000269|PubMed:4019786}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, insulin-dependent, 2 (IDDM2) [MIM:125852]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:18192540}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, permanent neonatal (PNDM) [MIM:606176]: A rare form of diabetes distinct from childhood- onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy. {ECO:0000269|PubMed:17855560, ECO:0000269|PubMed:18162506}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Maturity-onset diabetes of the young 10 (MODY10) [MIM:613370]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:18162506, ECO:0000269|PubMed:18192540, ECO:0000269|PubMed:20226046, ECO:0000269|PubMed:25423173}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0384
- RVIS EVS
- -0.08
- RVIS percentile EVS
- 47.79
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.968
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Low | Low | Low |