SH2B1

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

Basic information

Region (hg38): 16:28846599-28874212

Links

ENSG00000178188 ∙ NCBI:25970 ∙ OMIM:608937 ∙ HGNC:30417 ∙ Uniprot:Q9NRF2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency (Moderate), mode of inheritance: AD
• severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency (Supportive), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SH2B1 gene.

• not provided (99 variants)
• SH2B1-related condition (27 variants)
• Inborn genetic diseases (23 variants)
• not specified (2 variants)
• Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency (1 variants)
• Premature ovarian failure (1 variants)
• SH2B1-associated disorder (1 variants)
• Distal 16p11.2 microdeletion syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SH2B1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	31	4	37
missense			80	6	3	89
nonsense	1					1
start loss						0
frameshift			6			6
inframe indel			1			1
splice donor/acceptor (+/-2bp)			2			2
splice region				1	2	3
non coding				1	1	2
Total	1	0	91	38	8

Variants in SH2B1

This is a list of pathogenic ClinVar variants found in the SH2B1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-28865303-G-A		SH2B1-related disorder	Likely benign (Oct 12, 2022)
16-28866105-C-T		not specified	Uncertain significance (Aug 14, 2023)
16-28866133-C-T		SH2B1-related disorder	Likely benign (Feb 07, 2024)
16-28866136-G-A		SH2B1-related disorder	Likely benign (Oct 09, 2020)
16-28866145-G-C		SH2B1-related disorder	Likely benign (May 03, 2021)
16-28866148-G-A		SH2B1-related disorder	Likely benign (Dec 20, 2021)
16-28866154-A-C		SH2B1-related disorder	Benign/Likely benign (Oct 09, 2023)
16-28866155-C-T		SH2B1-related disorder	Uncertain significance (Jan 29, 2024)
16-28866157-C-T		SH2B1-related disorder	Likely benign (Jul 14, 2022)
16-28866159-C-A		not specified	Uncertain significance (Aug 09, 2021)
16-28866160-G-A		SH2B1-related disorder	Likely benign (Nov 10, 2023)
16-28866160-G-C		SH2B1-related disorder	Likely benign (Nov 04, 2021)
16-28866163-C-A		SH2B1-related disorder	Likely benign (Aug 16, 2021)
16-28866166-T-G		SH2B1-related disorder	Likely benign (Apr 25, 2022)
16-28866167-A-T		not specified	Uncertain significance (Aug 15, 2023)
16-28866173-C-T			Uncertain significance (Oct 27, 2023)
16-28866174-G-A		SH2B1-related disorder • not specified	Uncertain significance (Dec 06, 2023)
16-28866193-C-T		SH2B1-related disorder	Likely benign (Oct 17, 2019)
16-28866203-G-A		not specified	Uncertain significance (Aug 10, 2021)
16-28866205-G-T		SH2B1-related disorder	Likely benign (Jan 07, 2024)
16-28866213-A-ACTTTGCCCGC			Uncertain significance (Mar 26, 2020)
16-28866221-C-A			Uncertain significance (Sep 06, 2023)
16-28866221-C-T		SH2B1-related disorder	Uncertain significance (Feb 06, 2024)
16-28866231-G-A		not specified	Uncertain significance (Oct 27, 2021)
16-28866235-C-CT			Uncertain significance (Mar 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SH2B1	protein_coding	protein_coding	ENST00000322610	8	27606

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.969	0.0314	125732	0	7	125739	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.691	415	457	0.909	0.0000287	4719
Missense in Polyphen		109	161.03	0.67688		1687
Synonymous	0.286	196	201	0.974	0.0000132	1734
Loss of Function	4.24	4	28.4	0.141	0.00000160	298

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.000110	0.0000924
European (Non-Finnish)	0.0000375	0.0000352
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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}.
• Pathway: Neurotrophin signaling pathway - Homo sapiens (human);JAK-STAT-Ncore;Leptin signaling pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;JAK-STAT;Signal Transduction;Prolactin receptor signaling;Prolactin;Cytokine Signaling in Immune system;Factors involved in megakaryocyte development and platelet production;Immune System;BDNF;EGFR1;Hemostasis;Signaling by Leptin;Leptin;Neurotrophic factor-mediated Trk receptor signaling (Consensus)

Recessive Scores

• pRec: 0.235

Intolerance Scores

• loftool: 0.667
• rvis_EVS: -0.24
• rvis_percentile_EVS: 36.17

Haploinsufficiency Scores

• pHI: 0.503
• hipred: Y
• hipred_score: 0.750
• ghis: 0.588

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.865

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sh2b1
• Phenotype: growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype

Gene ontology

• Biological process: transmembrane receptor protein tyrosine kinase signaling pathway;blood coagulation;positive regulation of signal transduction;lamellipodium assembly;intracellular signal transduction;positive regulation of mitotic nuclear division;regulation of DNA biosynthetic process
• Cellular component: nucleus;cytosol;plasma membrane
• Molecular function: transmembrane receptor protein tyrosine kinase adaptor activity;protein binding