HAND2

heart and neural crest derivatives expressed 2, the group of Basic helix-loop-helix proteins

Basic information

Region (hg38): 4:173524969-173530229

Links

ENSG00000164107 ∙ NCBI:9464 ∙ OMIM:602407 ∙ HGNC:4808 ∙ Uniprot:P61296 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• HAND2 related congenital heart defect (Moderate), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HAND2 gene.

• Dilated cardiomyopathy 1A (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HAND2 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				6	4	10
missense			24	3	1	28
nonsense	1		1			2
start loss						0
frameshift			1			1
inframe indel			6			6
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				1		1
Total	1	0	32	10	5

Variants in HAND2

This is a list of pathogenic ClinVar variants found in the HAND2 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-173527281-T-G			Likely benign (Apr 07, 2023)
4-173527283-C-G		Inborn genetic diseases	Uncertain significance (Apr 06, 2024)
4-173527284-T-C			Uncertain significance (Aug 10, 2022)
4-173527337-C-G			Uncertain significance (Jun 22, 2022)
4-173527346-G-T			Uncertain significance (Dec 10, 2023)
4-173527357-T-G		Inborn genetic diseases	Uncertain significance (May 01, 2024)
4-173527393-G-C			Benign/Likely benign (Jan 14, 2024)
4-173528787-T-C			Uncertain significance (Oct 01, 2021)
4-173528798-C-T		HAND2-related disorder	Likely benign (Jun 15, 2023)
4-173528806-C-T		Inborn genetic diseases	Uncertain significance (May 22, 2023)
4-173528831-G-A			Benign (May 21, 2022)
4-173528882-GGA-G			Uncertain significance (Jun 23, 2022)
4-173528900-G-T			Likely pathogenic (-)
4-173528905-C-T		HAND2-related disorder	Uncertain significance (Mar 02, 2023)
4-173528907-T-C		Inborn genetic diseases	Uncertain significance (Mar 28, 2023)
4-173528925-A-G			Uncertain significance (Apr 09, 2021)
4-173528966-C-T		HAND2-related disorder	Likely benign (Mar 16, 2023)
4-173528999-C-T			Benign (Dec 24, 2021)
4-173529000-G-C		HAND2-related disorder	Uncertain significance (Mar 07, 2023)
4-173529007-G-C			Uncertain significance (Aug 22, 2022)
4-173529007-GC-G		HAND2-related disorder	Uncertain significance (Mar 04, 2024)
4-173529013-C-A			Uncertain significance (Jan 01, 2023)
4-173529013-C-G		Inborn genetic diseases	Uncertain significance (Jun 09, 2022)
4-173529021-G-C			Likely benign (Sep 30, 2023)
4-173529028-C-T		Inborn genetic diseases	Uncertain significance (Aug 19, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HAND2	protein_coding	protein_coding	ENST00000359562	2	5261

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.399	0.565	125613	0	1	125614	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.18	74	109	0.681	0.00000498	1396
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: Heart Development;TarBasePathway;miR-targeted genes in epithelium - TarBase;Transcriptional regulation by RUNX2;Gene expression (Transcription);nfat and hypertrophy of the heart ;Generic Transcription Pathway;RNA Polymerase II Transcription (Consensus)

Recessive Scores

• pRec: 0.292

Haploinsufficiency Scores

• pHI: 0.650
• hipred: Y
• hipred_score: 0.742
• ghis: 0.607

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.892

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hand2
• Phenotype: immune system phenotype; skeleton phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; digestive/alimentary 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); normal phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); embryo phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: hand2
• Affected structure: cardiac muscle cell
• Phenotype tag: abnormal
• Phenotype quality: organization quality

Gene ontology

• Biological process: angiogenesis;in utero embryonic development;heart looping;suckling behavior;cardiac right ventricle formation;cardiac neural crest cell migration involved in outflow tract morphogenesis;regulation of secondary heart field cardioblast proliferation;apoptotic process involved in heart morphogenesis;noradrenergic neuron differentiation;heart development;adult heart development;mesenchymal cell proliferation;positive regulation of cardiac muscle hypertrophy;positive regulation of gene expression;negative regulation of gene expression;negative regulation of cardiac muscle cell apoptotic process;regulation of tissue remodeling;odontogenesis of dentin-containing tooth;embryonic digit morphogenesis;negative regulation of DNA binding;negative regulation of DNA-binding transcription factor activity;tongue development;negative regulation of osteoblast differentiation;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;sympathetic nervous system development;thymus development;peripheral nervous system neuron development;cartilage morphogenesis;coronary artery morphogenesis;visceral serous pericardium development;cardiac neural crest cell development involved in outflow tract morphogenesis;cell proliferation involved in outflow tract morphogenesis;positive regulation of ERK1 and ERK2 cascade;positive regulation of p38MAPK cascade;primary palate development;positive regulation of transcription regulatory region DNA binding;positive regulation of transcription from RNA polymerase II promoter involved in norepinephrine biosynthetic process;positive regulation of semaphorin-plexin signaling pathway involved in outflow tract morphogenesis
• Cellular component: nuclear chromatin;transcription factor complex;protein-containing complex
• 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;transcription factor binding;activating transcription factor binding;protein homodimerization activity;transcription regulatory region DNA binding;protein heterodimerization activity;E-box binding