HAND2
protein-codingheart and neural crest derivatives expressed 2, the group of Basic helix-loop-helix proteins
Gene summary
The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, this transcription factor plays an important role in limb and branchial arch development. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0800476
Submitter: ClinGen
*HAND2* was first reported in relation to autosomal dominant structural congenital heart disease HAND2-related in 2015 (Lu et al., 2015; PMID: 26676105). Two variants (missense variants that cause loss of function) that have been reported in two probands in two publications (PMIDs: 26676105, 26865696) are included in this curation. Variants associated with isolated dilated cardiomyopathy are excluded. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence (mouse models, expression studies, biochemical functional evidence, and interaction evidence; PMIDs: 9171826, 9878849, 10675351, 11812799, 15576406, 26676105). In summary, there is moderate evidence supporting the relationship between *HAND2* and autosomal dominant structural congenital heart disease. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was initially approved by the ClinGen Congenital Heart Disease GCEP on the meeting date July 11, 2023 (SOP Version 9). It was re-evaluated on April 13, 2026 (SOP Version 12). One new case of genetic evidence was found (PMID: 40378586), but not scored due to the variant allele frequency in gnomAD. As a result of this reevaluation, the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0000119
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HAND2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021973.3. 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 | 1 | 16 | 17 | |||
| missense | 43 | 6 | 1 | 50 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 6 | 6 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 1 | 50 | 22 | 1 | 75 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_068808.1 | 2 | MANE Select | |
| Ensembl | ENSP00000352565.4 | 2 | MANE Select | |
| Ensembl | ENSP00000427084.1 | 2 | Standard | |
| Ensembl | ENSP00000808758.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hand2 | Danio rerio | Structure: cardiac muscle cell Quality: organization quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Heart Development
- TarBasePathway
- miR-targeted genes in epithelium - TarBase
- Transcriptional regulation by RUNX2
- Gene expression (Transcription)
Biological Process
- angiogenesis
- in utero embryonic development
- heart looping
- suckling behavior
- cardiac right ventricle formation
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- AT DNA binding
- protein binding
Cellular Component
- nuclear chromatin
- transcription factor complex
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000359562
- Coding exons
- 2
- Length
- 5261
- Individuals with no LoFs
- 125613
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125614
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.18 | 74 | 109 | 0.681 | 0.00000498 | 1396 |
| Missense (PolyPhen) | 13 | 40.527 | 0.32078 | 462 | ||
| Synonymous | -0.580 | 51 | 46.0 | 1.11 | 0.00000226 | 427 |
| Loss of Function | 1.67 | 1 | 5.03 | 0.199 | 2.18e-7 | 71 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| 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: Essential for cardiac morphogenesis, particularly for the formation of the right ventricle and of the aortic arch arteries. Required for vascular development and regulation of angiogenesis, possibly through a VEGF signaling pathway. Plays also an important role in limb development, particularly in the establishment of anterior-posterior polarization, acting as an upstream regulator of sonic hedgehog (SHH) induction in the limb bud. Is involved in the development of branchial arches, which give rise to unique structures in the head and neck. Binds DNA on E-box consensus sequence 5'-CANNTG-3' (By similarity). {ECO:0000250}.;
Recessive Scores
- pRec
- 0.292
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.892
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |