HEY2

protein-coding

hes related family bHLH transcription factor with YRPW motif 2, the group of Basic helix-loop-helix proteins

Gene summary

This gene encodes a member of the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcription factors. The encoded protein forms homo- or hetero-dimers that localize to the nucleus and interact with a histone deacetylase complex to repress transcription. Expression of this gene is induced by the Notch signal transduction pathway. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

MANE transcript

NM_012259.3

Inheritance

AD, SD

ClinVar variants

P:1U:51B:4

Top phenotype

familial thoracic aortic aneurysm and aortic dissection

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr6:125,747,664-125,761,269

External References & Databases

Ensembl (ENSG00000135547)

Transcript & Mutation Effects

hg38 • Region Span ~13.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*HEY2* was first reported in relation to autosomal dominant congenital heart disease in 2020 (Edwards et al., PMID: 32368696). 9 variants (missense, nonsense, frameshift, in-frame deletion) that have been reported in at least 12 probands in 2 publications (PMIDs: 32820247, 32368696) are included in this curation. The gene shows a dosage effect, with mostly heterozygous cases reported, although there is a family with three homozygotes severely affected and heterozygous individuals with a milder phenotype. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (NCBI fetal expression data, interaction evidence; PMID: 16199874 ). *HEY2* is shown to inhibit *GATA4* and *GATA6* expression and function. *GATA4* has been classified as definitive for autosomal dominant structural congenital heart disease. *GATA6* has been classified as definitive for autosomal dominant congenital heart disease with or without pancreatic agenesis or neonatal diabetes. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 7/2/2024 (SOP Version 10).

congenital heart diseaseLIMITED

Inheritance Pattern: SD

Disease ID:MONDO:0005453

Submitter: PanelApp Australia

familial thoracic aortic aneurysm and aortic dissectionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: Orphanet

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HEY2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 51

not providedTotal: 5

Tetralogy of FallotTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012259.3. 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			2 clinvar	1 clinvar	1 clinvar	4
missense	1 clinvar		48 clinvar	2 clinvar		51
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	1	0	51	3	1	56

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012259.3	RefSeq	NP_036391.1	5	MANE Select
ENST00000368364.4	Ensembl	ENSP00000357348.3	5	MANE Select
ENST00000368365.5	Ensembl	ENSP00000357349.1	4	Standard
ENST00000368365.6	Ensembl	ENSP00000357349.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hey2	Danio rerio	Structure: pronephric glomerular capillary Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

hey2

Danio rerio

Structure: pronephric glomerular capillary

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Breast cancer - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)
Heart Development
Signaling by NOTCH1

Biological Process

negative regulation of transcription by RNA polymerase II
blood vessel development
vasculogenesis
muscular septum morphogenesis
outflow tract morphogenesis

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II activating transcription factor binding
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
cytoplasm
Sin3 complex
transcriptional repressor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368364
Coding exons: 5
Length: 13606
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.854	182	217	0.837	0.0000135	2141
Missense (PolyPhen)		50	75.523	0.66205		716
Synonymous	0.307	91	94.8	0.960	0.00000710	722
Loss of Function	2.89	1	11.7	0.0858	6.64e-7	129

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000036	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Downstream effector of Notch signaling which may be required for cardiovascular development. Transcriptional repressor which binds preferentially to the canonical E box sequence 5'- CACGTG-3'. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6. {ECO:0000269|PubMed:10692439, ECO:0000269|PubMed:11095750, ECO:0000269|PubMed:15485867, ECO:0000269|PubMed:16293227}.;

Recessive Scores

pRec: 0.180

Intolerance Scores

LoFtool: 0.383
RVIS EVS: -0.4
RVIS percentile EVS: 26.53

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	Medium
Cancer	Medium	Medium	Medium