GeneBe

SH2B1

protein-coding

SH2B adaptor protein 1, the group of SH2 domain containing|Pleckstrin homology domain containing

Gene summary

This gene encodes a member of the SH2-domain containing mediators family. The encoded protein mediates activation of various kinases and may function in cytokine and growth factor receptor signaling and cellular transformation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

MANE transcript

NM_001387430.1

Inheritance

AR, AD

ClinVar variants

P:2U:259B:119

Top phenotype

severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr16:28,846,600-28,874,212

External References & Databases

Ensembl (ENSG00000178188)NCBI Gene (25970)OMIM (608937)HGNC:30417GenCCUniProt (Q9NRF2)AlphaFoldClinVar (SH2B1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~27.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0017994

Submitter: LiferaOmics

Genetic Evidence- Published (AD context; not scored for AR) PMID: 23160192 – Reports heterozygous SH2B1 variants in individuals with severe early-onset obesity, frequently inherited from overweight/obese parents. The data support a dominant or semi-dominant inheritance pattern rather than autosomal recessive disease. PMID: 29216354 – Identifies rare heterozygous SH2B1 variants in obesity cohorts; no biallelic cases reported. PMID: 26031769 – Variant frequency study in obese and lean individuals; heterozygous variants observed without Mendelian segregation consistent with AR. These publications primarily support a heterozygous (AD/complex) context and therefore are not scorable under the AR model. AD-context evidence total (not scored for AR) = 0 Genetic evidence – Published (AR scope) PMID: 24971614 – Family 1 – one proband. Case-level (biallelic non-LOF in AR model; homozygous; no consanguinity reported) = 0.1; Segregation = 0; Case-control = 0 Family 1 total = 0.1 Published genetic evidence total = 0.1 / 12 Genetic evidence – Our cases Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Total genetic evidence (published AR + our cases) 1.0 (published AR) + 1.0 (our case) = 1.1 / 12 Experimental evidence – Published PMID: 31439647 – Demonstrates that perturbation of SH2B1 domains in vivo leads to obesity and insulin resistance in mouse models, supporting a loss-of-function mechanism relevant to energy homeostasis. Model system evidence = 1.5 PMID: 24971614 – Functional characterization of SH2B1 variants in engineered cellular systems demonstrating altered protein function and signaling impact. Functional alteration = 0.5 Foundational studies of SH2B1 in leptin/JAK2 signaling establish its critical role in metabolic regulation and energy balance, supporting biological plausibility for obesity phenotypes. Gene function / biological plausibility = 0.5 Experimental evidence total = 2.5 / 6 Overall score Genetic evidence = 1.1 Experimental evidence = 2.5 Overall score = 3.6 / 18

severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017994

Submitter: Orphanet

severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiencyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0017994

Submitter: Genomics England PanelApp

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SH2B1 variants in ClinVar

8 Conditions Cataloged
SH2B1-related disorderTotal: 272
not providedTotal: 164
not specifiedTotal: 97
Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiencyTotal: 2
Premature ovarian failureTotal: 1
SH2B1-associated disorderTotal: 1
Distal 16p11.2 microdeletion syndromeTotal: 1
SH2B1-associated obesityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001387430.1. 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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
107
clinvar
3
clinvar
 116
missense
1
clinvar
238
clinvar
8
clinvar
1
clinvar
 248
nonsense
1
clinvar
2
clinvar
 3
start loss
0
frameshift
10
clinvar
 10
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total022591154380

Highest pathogenic variant AF is 0.00017594945

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001387430.1RefSeqNP_001374359.18MANE Select
ENST00000684370.1EnsemblENSP00000507475.18MANE Select
NM_001145795.2RefSeqNP_001139267.18Standard
NM_001145796.2RefSeqNP_001139268.19Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neurotrophin signaling pathway - Homo sapiens (human)
  • JAK-STAT-Ncore
  • Leptin signaling pathway
  • Brain-Derived Neurotrophic Factor (BDNF) signaling pathway
  • JAK-STAT

Biological Process

  • transmembrane receptor protein tyrosine kinase signaling pathway
  • blood coagulation
  • positive regulation of signal transduction
  • lamellipodium assembly
  • intracellular signal transduction

Molecular Function

  • transmembrane receptor protein tyrosine kinase adaptor activity
  • protein binding

Cellular Component

  • nucleus
  • cytosol
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000322610
Coding exons
8
Length
27606
Individuals with no LoFs
125732
Homozygous LoFs
0
Heterozygous LoFs
7
Defined
125739
p
0.0000278
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6914154570.9090.00002874719
Missense (PolyPhen)109161.030.676881687
Synonymous0.2861962010.9740.00001321734
Loss of Function4.24428.40.1410.00000160298

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish0.000110.000092rare
European (Non-Finnish)0.0000380.000035rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on tyrosine residues. These phosphotyrosines form potential binding sites for other signaling proteins. GH also promotes serine/threonine phosphorylation of SH2B1 and these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP) signaling, binds to and potentiates the activation of JAK2 by globally enhancing downstream pathways. In response to leptin, binds simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-kinase pathway. Acts as positive regulator of NGF-mediated activation of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2 and of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2, the mechanism seems to involve dimerization of both, SH2B1 and JAK2. Enhances RET phosphorylation and kinase activity. Isoforms seem to be differentially involved in IGF-I and PDGF-induced mitogenesis (By similarity). {ECO:0000250, ECO:0000269|PubMed:11827956, ECO:0000269|PubMed:14565960, ECO:0000269|PubMed:15767667, ECO:0000269|PubMed:16569669, ECO:0000269|PubMed:17471236, ECO:0000269|PubMed:9694882, ECO:0000269|PubMed:9742218}.;

Recessive Scores

pRec
0.235

Intolerance Scores

LoFtool
0.667
RVIS EVS
-0.24
RVIS percentile EVS
36.17

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.865

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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