IGF2R

protein-coding

insulin like growth factor 2 receptor, the group of CD molecules|MRH domain containing

Gene summary

This gene encodes a receptor for both insulin-like growth factor 2 and mannose 6-phosphate. The binding sites for each ligand are located on different segments of the protein. This receptor has various functions, including in the intracellular trafficking of lysosomal enzymes, the activation of transforming growth factor beta, and the degradation of insulin-like growth factor 2. Mutation or loss of heterozygosity of this gene has been association with risk of hepatocellular carcinoma. The orthologous mouse gene is imprinted and shows exclusive expression from the maternal allele; however, imprinting of the human gene may be polymorphic, as only a minority of individuals showed biased expression from the maternal allele (PMID:8267611). [provided by RefSeq, Nov 2015]

MANE transcript

NM_000876.4

Inheritance

—

ClinVar variants

P:4U:318B:50

Top phenotype

Hepatocellular carcinoma

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr6:159,969,082-160,113,507

External References & Databases

Ensembl (ENSG00000197081)

Transcript & Mutation Effects

hg38 • Region Span ~144.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IGF2R variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 289

not providedTotal: 42

Hepatocellular carcinomaTotal: 5

Premature ovarian failureTotal: 1

Prostate cancerTotal: 1

Myoepithelial tumorTotal: 1

Beckwith-Wiedemann syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000876.4. 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			14 clinvar	17 clinvar	5 clinvar	36
missense	2 clinvar	1 clinvar	292 clinvar	18 clinvar	10 clinvar	323
nonsense			2 clinvar			2
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	2	2	318	35	15	372

Highest pathogenic variant AF is 0.000006824787

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000876.4	RefSeq	NP_000867.3	48	MANE Select
ENST00000356956.6	Ensembl	ENSP00000349437.1	48	MANE Select
ENST00000475834.2	Ensembl	ENSP00000473880.1	4	Standard
ENST00000676781.1	Ensembl	ENSP00000504419.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
Lysosome - Homo sapiens (human)
IGF-Ncore
miR-targeted genes in adipocytes - TarBase
miR-targeted genes in epithelium - TarBase

Biological Process

liver development
post-Golgi vesicle-mediated transport
receptor-mediated endocytosis
lysosomal transport
signal transduction

Molecular Function

G-protein alpha-subunit binding
retinoic acid binding
insulin-like growth factor-activated receptor activity
protein binding
insulin-like growth factor binding

Cellular Component

nuclear envelope lumen
lysosomal membrane
endosome
early endosome
late endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356956
Coding exons: 48
Length: 144409
Individuals with no LoFs: 125717
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125748
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.07	1203	1.42e+3	0.846	0.0000835	16329
Missense (PolyPhen)		347	503.96	0.68855		5625
Synonymous	-1.33	647	605	1.07	0.0000432	4796
Loss of Function	8.71	17	120	0.142	0.00000592	1464

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6- phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelyosomal compartment where the low pH mediates the dissociation of the complex. This receptor also binds IGF2. Acts as a positive regulator of T-cell coactivation, by binding DPP4. {ECO:0000269|PubMed:10900005}.;

Recessive Scores

pRec: 0.705

Intolerance Scores

LoFtool: 0.339
RVIS EVS: -1.93
RVIS percentile EVS: 1.9

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.977

Gene Damage Prediction

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