NKX2-5

NK2 homeobox 5, the group of NKL subclass homeoboxes and pseudogenes

Basic information

Region (hg38): 5:173232108-173235311

Previous symbols: [ "CSX", "NKX2E" ]

Links

ENSG00000183072 ∙ ∙ OMIM:600584 ∙ HGNC:2488 ∙ Uniprot:P52952 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• atrial septal defect 7 (Supportive), mode of inheritance: AD
• familial atrial fibrillation (Supportive), mode of inheritance: AD
• athyreosis (Supportive), mode of inheritance: AD
• familial isolated congenital asplenia (Supportive), mode of inheritance: AD
• familial bicuspid aortic valve (Supportive), mode of inheritance: AD
• atrial septal defect 7 (Strong), mode of inheritance: AD
• atrial septal defect 7 (Strong), mode of inheritance: AD
• hypothyroidism, congenital, nongoitrous, 5 (Limited), mode of inheritance: Unknown
• conotruncal heart malformations (Strong), mode of inheritance: AD
• dilated cardiomyopathy (Limited), mode of inheritance: AD
• NKX2.5-related congenital, conduction and myopathic heart disease (Definitive), mode of inheritance: AD
• atrial septal defect 7 (Definitive), mode of inheritance: AD
• tetralogy of fallot (Definitive), mode of inheritance: AD
• hypothyroidism, congenital, nongoitrous, 5 (Definitive), mode of inheritance: AD
• atrial septal defect 7 (Strong), mode of inheritance: AD
• atrial septal defect 7 (Strong), mode of inheritance: AD
• conotruncal heart malformations (Definitive), mode of inheritance: Semidominant
• hypothyroidism, congenital, nongoitrous, 5 (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Atrial septal defect 7, with or without AV conduction defects; Conotruncal heart malformations; Hypothyroidism, congenital nongoitrous, 5; Hypoplastic left heart syndrome 2; Ventricular septal defect 3; Conotruncal heart malformations, variable; Tetralogy of Fallot	AD	Cardiovascular; Endocrine	Individuals may have arrhythmias as well as congenital cardiac malformations (and can have arrhthymias without obvious structural cardiac malformations), and surveillance and treatment may be beneficial; In Hypothyroidism, congenital nongoitrous, medical treatment for thyroid insufficiency may be effective, and individuals may also be at risk for cardiac anomalies	Cardiovascular; Endocrine	1260978; 9651244; 10587520; 11714651; 12414819; 14607454; 15810002; 16418214; 16896344; 20659440; 21110066; 19948535; 20456451; 21637914

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NKX2-5 gene.

• Atrial septal defect 7 (359 variants)
• Cardiovascular phenotype (182 variants)
• not provided (117 variants)
• 6 conditions (36 variants)
• not specified (30 variants)
• Inborn genetic diseases (6 variants)
• Tetralogy of Fallot (6 variants)
• Abnormal cardiovascular system morphology (4 variants)
• Hypothyroidism, congenital, nongoitrous, 5 (4 variants)
• Ventricular septal defect 3 (3 variants)
• NKX2-5-related condition (3 variants)
• Congenital heart disease (2 variants)
• Malformation of the heart and great vessels (2 variants)
• Heart, malformation of (2 variants)
• Lissencephaly due to TUBA1A mutation (1 variants)
• Atrial septal defect 7;Ventricular septal defect 3 (1 variants)
• Double outlet right ventricle (1 variants)
• Atrial septal defect (1 variants)
• Long QT syndrome (1 variants)
• small Atrial septal defect;Single ventricle (1 variants)
• Primary dilated cardiomyopathy (1 variants)
• Familial isolated congenital asplenia (1 variants)
• Conotruncal heart malformations (1 variants)
• Primary dilated cardiomyopathy;Ventricular fibrillation;Atrial septal defect;Noncompaction cardiomyopathy (1 variants)
• Hypertrophic cardiomyopathy (1 variants)
• Hypoplastic left heart syndrome 2 (1 variants)
• Aortic arch interruption (1 variants)
• Truncus arteriosus (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NKX2-5 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				119	5	124
missense	6	4	250	6		266
nonsense	15	1	4			20
start loss						0
frameshift	34	7	1			42
inframe indel			11			11
splice donor/acceptor (+/-2bp)						0
splice region			1	1		2
non coding	1	2	3	14	12	32
Total	56	14	269	139	17

Highest pathogenic variant AF is 0.00000672

Variants in NKX2-5

This is a list of pathogenic ClinVar variants found in the NKX2-5 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-173232273-C-G		Atrial septal defect 7	Benign (Apr 05, 2023)
5-173232372-C-G			Likely benign (Jul 15, 2018)
5-173232508-C-A		not specified	Benign (Jun 15, 2018)
5-173232575-G-A		Atrial septal defect 7 • Cardiovascular phenotype	Likely benign (Dec 09, 2021)
5-173232576-G-C		Atrial septal defect 7	Uncertain significance (Jul 28, 2021)
5-173232578-T-C		Atrial septal defect 7	Likely benign (May 24, 2023)
5-173232583-T-C		Cardiovascular phenotype	Uncertain significance (Sep 11, 2023)
5-173232587-A-G		Atrial septal defect 7 • Cardiovascular phenotype	Likely benign (Dec 04, 2023)
5-173232587-A-T		Atrial septal defect 7	Uncertain significance (Nov 22, 2023)
5-173232588-T-C		Cardiovascular phenotype • Atrial septal defect 7	Uncertain significance (Jul 17, 2023)
5-173232591-AG-GC		Atrial septal defect 7	Uncertain significance (Aug 20, 2018)
5-173232594-G-A		Atrial septal defect 7 • Cardiovascular phenotype	Uncertain significance (Feb 28, 2023)
5-173232597-G-T		Atrial septal defect 7	Uncertain significance (Jan 24, 2024)
5-173232599-C-G		Cardiovascular phenotype	Likely benign (May 24, 2022)
5-173232601-C-A		Atrial septal defect 7 • not specified	Conflicting classifications of pathogenicity (Dec 21, 2023)
5-173232603-C-T		Atrial septal defect 7	Uncertain significance (Nov 08, 2023)
5-173232604-C-A		Atrial septal defect 7	Uncertain significance (Aug 09, 2022)
5-173232605-C-T		Atrial septal defect 7 • Cardiovascular phenotype	Likely benign (Nov 01, 2022)
5-173232606-G-A			Uncertain significance (Jan 07, 2016)
5-173232612-C-T		Cardiovascular phenotype • Atrial septal defect 7	Uncertain significance (Jun 09, 2023)
5-173232613-T-C		Cardiovascular phenotype	Likely benign (Feb 25, 2023)
5-173232613-T-G		Atrial septal defect 7	Uncertain significance (Jan 20, 2023)
5-173232616-G-A			Uncertain significance (May 13, 2022)
5-173232618-G-A		Atrial septal defect 7	Uncertain significance (Sep 03, 2022)
5-173232621-A-G		Atrial septal defect 7	Uncertain significance (Nov 16, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NKX2-5	protein_coding	protein_coding	ENST00000329198	2	3249

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.945	0.0545	125234	0	13	125247	0.0000519

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.199	178	186	0.959	0.00000860	1991
Missense in Polyphen		54	70.872	0.76193		747
Synonymous	-0.0159	90	89.8	1.00	0.00000438	728
Loss of Function	2.81	0	9.18	0.00	3.93e-7	108

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000347	0.000347
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000186	0.00000885
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Implicated in commitment to and/or differentiation of the myocardial lineage. Acts as a transcriptional activator of ANF in cooperation with GATA4 (By similarity). Binds to the core DNA motif of NPPA promoter (PubMed:22849347, PubMed:26926761). It is transcriptionally controlled by PBX1 and acts as a transcriptional repressor of CDKN2B (By similarity). It is required for spleen development. {ECO:0000250|UniProtKB:P42582, ECO:0000269|PubMed:22560297, ECO:0000269|PubMed:22849347, ECO:0000269|PubMed:26926761}.
• Disease: DISEASE: Atrial septal defect 7, with or without atrioventricular conduction defects (ASD7) [MIM:108900]: A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria, and atrioventricular conduction defects in some cases. {ECO:0000269|PubMed:10587520, ECO:0000269|PubMed:14607454, ECO:0000269|PubMed:15342699, ECO:0000269|PubMed:15810002, ECO:0000269|PubMed:9651244}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tetralogy of Fallot (TOF) [MIM:187500]: A congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. In this condition, blood from both ventricles (oxygen-rich and oxygen-poor) is pumped into the body often causing cyanosis. {ECO:0000269|PubMed:10587520, ECO:0000269|PubMed:11714651, ECO:0000269|PubMed:14607454}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Conotruncal heart malformations (CTHM) [MIM:217095]: A group of congenital heart defects involving the outflow tracts. Examples include truncus arteriosus communis, double-outlet right ventricle and transposition of great arteries. Truncus arteriosus communis is characterized by a single outflow tract instead of a separate aorta and pulmonary artery. In transposition of the great arteries, the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. In double outlet of the right ventricle, both the pulmonary artery and aorta arise from the right ventricle. {ECO:0000269|PubMed:14607454, ECO:0000269|PubMed:17891434}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypothyroidism, congenital, non-goitrous, 5 (CHNG5) [MIM:225250]: A non-autoimmune condition characterized by resistance to thyroid-stimulating hormone (TSH) leading to increased levels of plasma TSH and low levels of thyroid hormone. CHNG5 presents variable severity depending on the completeness of the defect. Most patients are euthyroid and asymptomatic, with a normal sized thyroid gland. Only a subset of patients develop hypothyroidism and present a hypoplastic thyroid gland. {ECO:0000269|PubMed:16418214}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ventricular septal defect 3 (VSD3) [MIM:614432]: A common form of congenital cardiovascular anomaly that may occur alone or in combination with other cardiac malformations. It can affect any portion of the ventricular septum, resulting in abnormal communications between the two lower chambers of the heart. Classification is based on location of the communication, such as perimembranous, inlet, outlet (infundibular), central muscular, marginal muscular, or apical muscular defect. Large defects that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death. {ECO:0000269|PubMed:21110066, ECO:0000269|PubMed:21165553}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypoplastic left heart syndrome 2 (HLHS2) [MIM:614435]: A syndrome due to defective development of the aorta proximal to the entrance of the ductus arteriosus, and hypoplasia of the left ventricle and mitral valve. As a result of the abnormal circulation, the ductus arteriosus and foramen ovale are patent and the right atrium, right ventricle, and pulmonary artery are enlarged. {ECO:0000269|PubMed:14607454, ECO:0000269|PubMed:15810002}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Heart Development;SRF and miRs in Smooth Muscle Differentiation and Proliferation;Cardiac Progenitor Differentiation;hop pathway in cardiac development;alk in cardiac myocytes;nfat and hypertrophy of the heart ;Regulation of nuclear SMAD2/3 signaling (Consensus)

Recessive Scores

• pRec: 0.479

Intolerance Scores

• loftool: 0.0374
• rvis_EVS: -0.1
• rvis_percentile_EVS: 46.49

Haploinsufficiency Scores

• pHI: 0.624
• hipred: Y
• hipred_score: 0.875

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.940

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nkx2-5
• Phenotype: craniofacial phenotype; muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region 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); hematopoietic system phenotype; normal phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); 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); digestive/alimentary 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); immune system phenotype; respiratory system phenotype; embryo phenotype

Zebrafish Information Network

• Gene name: nkx2.5
• Affected structure: cardiac muscle myoblast
• Phenotype tag: abnormal
• Phenotype quality: disrupted

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;vasculogenesis;heart looping;heart morphogenesis;outflow tract septum morphogenesis;cardiac conduction system development;bundle of His development;Purkinje myocyte differentiation;cardiac ventricle formation;right ventricular cardiac muscle tissue morphogenesis;ventricular trabecula myocardium morphogenesis;apoptotic process involved in heart morphogenesis;septum secundum development;proepicardium development;pulmonary myocardium development;adult heart development;positive regulation of cell population proliferation;negative regulation of cardiac muscle cell apoptotic process;positive regulation of transcription via serum response element binding;positive regulation of sodium ion transport;negative regulation of myotube differentiation;hemopoiesis;cell differentiation;BMP signaling pathway;thyroid gland development;embryonic heart tube development;negative regulation of apoptotic process;sarcomere organization;positive regulation of neuron differentiation;positive regulation of heart contraction;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;spleen development;positive regulation of cardioblast differentiation;ventricular cardiac myofibril assembly;cardiac muscle cell differentiation;cardiac muscle tissue morphogenesis;atrial cardiac muscle cell development;ventricular cardiac muscle cell development;regulation of cardiac muscle contraction;pharyngeal system development;cardiac muscle cell proliferation;regulation of cardiac muscle cell proliferation;cardiac muscle contraction;canonical Wnt signaling pathway;positive regulation of transcription initiation from RNA polymerase II promoter;heart trabecula formation;ventricular septum morphogenesis;atrial septum morphogenesis;atrioventricular node cell development;atrioventricular node cell fate commitment;embryonic heart tube left/right pattern formation;negative regulation of canonical Wnt signaling pathway;regulation of cardiac conduction
• Cellular component: nucleus;transcription factor complex;cytoplasm;protein-containing complex;protein-DNA complex;RNA polymerase II transcription factor complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;chromatin binding;DNA-binding transcription factor activity;protein binding;transcription factor binding;serum response element binding;protein homodimerization activity;sequence-specific DNA binding;transcription regulatory region DNA binding;protein heterodimerization activity