IGF2
protein-codinginsulin like growth factor 2, the group of Neuropeptides|MicroRNA protein coding host genes
Gene summary
This gene encodes a member of the insulin family of polypeptide growth factors, which are involved in development and growth. It is an imprinted gene, expressed only from the paternal allele, and epigenetic changes at this locus are associated with Wilms tumour, Beckwith-Wiedemann syndrome, rhabdomyosarcoma, and Silver-Russell syndrome. A read-through INS-IGF2 gene exists, whose 5' region overlaps the INS gene and the 3' region overlaps this gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]
- C11orf43
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~29.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014663
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014663
Submitter: ClinGen
The IGF2 gene is located on chromosome 11p15.5 and encodes insulin-like growth factor 2, a protein hormone that regulates cell proliferation, growth, migration, differentiation, and survival. The protein binds and activates Insulin Receptor Tyrosine - A (IR-A) and IGF-1R. The receptor structural change leads to activation of the intracellular tyrosine kinase domain and autophosphorylation with an outcome of growth promoting effect (Blyth et al., 2020). The gene has 5 promoters that are differentially activated during pre and postnatal life. There are 9 exons in total however, only the last 3 exons are coding exons (Röttgering and Szuhai 2019). Additionally, IGF2 is a paternally expressed, maternally imprinted gene with an imprinting control region (ICR1) located between the H19 and IGF2 genes. IGF2 was first reported in relation to autosomal dominant Silver-Russell syndrome 3 in 2015 (Begemann et al., PMID: 26154720). Silver-Russell Syndrome 3 is caused by heterozygosity pathogenic variants in the paternal copy of the IGF2 gene. Features seen in Silver-Russell syndrome 3 patients include intrauterine growth retardation with relative macrocephaly, feeding difficulties, growth restriction, triangular face, prominent forehead, low-set ears, limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay. Thirteen variants (5 missense, 3 frameshifts, 3 splice site, 2 nonsense) reported in thirteen probands in eight publications (PMIDs: 26154720, 28848601,28489339, 30152198, 28796236, 30400067, 31803239, 31544945) are include in this curation. The most common mechanism of disease is loss of methylation at the chromosome 11p15. A total of 10.6 pts for genetic evidence was reached, considering case-level data. This gene-disease relationship is supported by expression, biochemical, and two mouse models (PMIDs: 33567274, 2621730, 32459985, 2330056). In summary, there is definitive evidence supporting the relationship between IGF2 and autosomal dominant Silver-Russell Syndrome 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 10/04/2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0014663
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014663
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014663
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0016475
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic
Intervention: Cardiovascular; Endocrine
Rationale: Among other findings, response to growth hormone therapy has been described, and awareness may allow early diagnosis and management of this issue; The condition can involve congenital cardiac anomalies, and awareness may allow early management
Comments: Imprinting has been implicated in the inheritance pattern
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IGF2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000612.6. 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 | 1 | 37 | 2 | 40 | ||
| missense | 1 | 7 | 77 | 9 | 94 | |
| nonsense | 4 | 4 | 8 | |||
| start loss | 2 | 2 | ||||
| frameshift | 5 | 4 | 8 | 17 | ||
| splice donor/acceptor (+/-2bp) | 3 | 1 | 4 | |||
| Total | 13 | 15 | 89 | 46 | 2 | 165 |
Highest pathogenic variant AF is 6.9702537e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000603.1 | 3 | MANE Select | |
| Ensembl | ENSP00000414497.2 | 3 | MANE Select | |
| RefSeq | NP_001007140.2 | 3 | Standard | |
| RefSeq | NP_001121070.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| igf2a | Danio rerio | Structure: spinal cord neural keel Quality: apoptotic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Hepatocellular carcinoma - Homo sapiens (human)
- Ras signaling pathway - Homo sapiens (human)
- MAPK signaling pathway - Homo sapiens (human)
- Proteoglycans in cancer - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- skeletal system development
- osteoblast differentiation
- in utero embryonic development
- embryonic placenta development
Molecular Function
- insulin receptor binding
- insulin-like growth factor receptor binding
- integrin binding
- hormone activity
- protein binding
Cellular Component
- extracellular region
- extracellular space
- platelet alpha granule lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000434045
- Coding exons
- 4
- Length
- 20492
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.931 | 127 | 160 | 0.793 | 0.0000104 | 1509 |
| Missense (PolyPhen) | 41 | 55.948 | 0.73283 | 492 | ||
| Synonymous | -0.0161 | 66 | 65.8 | 1.00 | 0.00000448 | 503 |
| Loss of Function | 1.36 | 3 | 6.84 | 0.439 | 2.91e-7 | 81 |
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 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: The insulin-like growth factors possess growth-promoting activity. Major fetal growth hormone in mammals. Plays a key role in regulating fetoplacental development. IGF-II is influenced by placental lactogen. Also involved in tissue differentiation. Positively regulates myogenic transcription factor MYOD1 function by facilitating the recruitment of transcriptional coactivators, thereby controlling muscle terminal differentiation (By similarity). In adults, involved in glucose metabolism in adipose tissue, skeletal muscle and liver (Probable). Acts as a ligand for integrin which is required for IGF2 signaling (PubMed:28873464). {ECO:0000250|UniProtKB:P09535, ECO:0000269|PubMed:28873464, ECO:0000305|PubMed:24593700}.;
- Disease
- DISEASE: Silver-Russell syndrome (SRS) [MIM:180860]: A clinically heterogeneous condition characterized by severe intrauterine growth retardation, poor postnatal growth, craniofacial features such as a triangular shaped face and a broad forehead, body asymmetry, and a variety of minor malformations. The phenotypic expression changes during childhood and adolescence, with the facial features and asymmetry usually becoming more subtle with age. {ECO:0000269|PubMed:19066168}. Note=The gene represented in this entry is involved in disease pathogenesis. Most of the cases of Silver-Russell syndrome are caused by the epigenetic changes of DNA hypomethylation at the telomeric imprinting control region (ICR1) on chromosome 11p15, involving the H19 and IGF2 genes.; DISEASE: Growth restriction, severe, with distinctive facies (GRDF) [MIM:616489]: A disease characterized by severe prenatal and postnatal growth restriction, facial dysmorphism, and short stature in the presence of normal or slightly elevated growth hormone levels. {ECO:0000269|PubMed:26154720}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0504
- RVIS EVS
- -0.27
- RVIS percentile EVS
- 34.32
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |