NKX2-1

NK2 homeobox 1, the group of NKL subclass homeoboxes and pseudogenes

Basic information

Region (hg38): 14:36516392-36521149

Previous symbols: [ "NKX2A", "BCH", "TITF1" ]

Links

ENSG00000136352 ∙ NCBI:7080 ∙ OMIM:600635 ∙ HGNC:11825 ∙ Uniprot:P43699 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary progressive chorea without dementia (Definitive), mode of inheritance: AD
• brain-lung-thyroid syndrome (Definitive), mode of inheritance: AD
• brain-lung-thyroid syndrome (Strong), mode of inheritance: AD
• hereditary progressive chorea without dementia (Strong), mode of inheritance: AD
• choreatic disease (Supportive), mode of inheritance: AD
• brain-lung-thyroid syndrome (Supportive), mode of inheritance: AD
• brain-lung-thyroid syndrome (Strong), mode of inheritance: AD
• NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction; Thyroid cancer, nonmedullary 1	AD	Allergy/Immunology/Infectious; Endocrine; Neurologic; Oncologic; Pulmonary	Individuals with Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction may have congenital hypothyroidism necessitating thyroxine replacement; Response to levodopa has also been reported; Neonates may require ventilatory support, and may be prone to recurrent respiratory infections, and awareness may allow prophylactic measures, as well as prompt and aggressive treatment of infections; For Thyroid cancer, nonmedullary 1, individuals have been described as being susceptible to nonmedullary thyroid cancer, and awareness may allow early surveillance, diagnosis, and management	Allergy/Immunology/Infectious; Endocrine; Neurologic; Oncologic; Pulmonary	9565498; 10931427; 11854319; 11854318; 11971878; 12891678; 15289765; 15955952; 19176457; 19336474; 22488412; 22825795
Choreoathetosis, hypothyroidism, and neonatal respiratory distress manifests in the childhood; Thyroid cancer, nonmedullary 4 has been reported as manifesting in adulthood

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NKX2-1 gene.

• not provided (33 variants)
• Brain-lung-thyroid syndrome (21 variants)
• Benign hereditary chorea (6 variants)
• Inborn genetic diseases (4 variants)
• NKX2-1-related disorder (3 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NKX2-1 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	41	2	49
missense	3	14	66	5	1	89
nonsense	18	10	1			29
start loss			1			1
frameshift	32	21	1			54
inframe indel		1	6	1		8
splice donor/acceptor (+/-2bp)	3					3
splice region	1		4	2		7
non coding	1	1	13	19	14	48
Total	57	47	94	66	17

Variants in NKX2-1

This is a list of pathogenic ClinVar variants found in the NKX2-1 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-36516458-T-C		Brain-lung-thyroid syndrome • Benign hereditary chorea	Uncertain significance (Jan 13, 2018)
14-36516552-C-G		Squamous cell carcinoma	Uncertain significance (Jun 06, 2022)
14-36516696-AG-A		Brain-lung-thyroid syndrome • Benign hereditary chorea	Likely benign (Jun 14, 2016)
14-36516699-G-C		Brain-lung-thyroid syndrome • Benign hereditary chorea	Benign (Jan 13, 2018)
14-36516701-G-A		Brain-lung-thyroid syndrome • Benign hereditary chorea	Uncertain significance (Jan 13, 2018)
14-36516734-C-T		Benign hereditary chorea • Brain-lung-thyroid syndrome	Uncertain significance (Jan 13, 2018)
14-36516742-G-A		Benign hereditary chorea • Brain-lung-thyroid syndrome	Uncertain significance (Jan 12, 2018)
14-36516808-T-C		Brain-lung-thyroid syndrome • Benign hereditary chorea	Uncertain significance (Jan 12, 2018)
14-36516817-CA-C		Brain-lung-thyroid syndrome • Benign hereditary chorea	Uncertain significance (Jun 14, 2016)
14-36516817-C-CA		Brain-lung-thyroid syndrome • Benign hereditary chorea	Uncertain significance (Jun 14, 2016)
14-36516817-C-CAA		Brain-lung-thyroid syndrome • Benign hereditary chorea	Uncertain significance (Jun 14, 2016)
14-36516842-T-G		Benign hereditary chorea • Brain-lung-thyroid syndrome	Benign (Jan 12, 2018)
14-36516974-CA-C		Lung adenocarcinoma	Benign (Jun 06, 2022)
14-36516985-A-AC		Brain-lung-thyroid syndrome • Benign hereditary chorea	Benign (Aug 14, 2018)
14-36517060-C-CT			Benign (Aug 11, 2018)
14-36517067-T-TA		Brain-lung-thyroid syndrome • Benign hereditary chorea	Conflicting classifications of pathogenicity (Jul 01, 2023)
14-36517068-A-T		Brain-lung-thyroid syndrome • Benign hereditary chorea	Benign (Aug 10, 2019)
14-36517069-A-T		Brain-lung-thyroid syndrome • Benign hereditary chorea	Benign (Jun 01, 2022)
14-36517091-A-AG		Brain-lung-thyroid syndrome • Benign hereditary chorea	Uncertain significance (Jun 14, 2016)
14-36517091-A-AGG		Benign hereditary chorea • Brain-lung-thyroid syndrome	Uncertain significance (Jun 14, 2016)
14-36517091-A-AGGGTG			Likely benign (Nov 01, 2022)
14-36517091-A-AGAGTGG			Likely benign (May 01, 2023)
14-36517091-A-AGGGTGG			Benign (Nov 01, 2019)
14-36517091-A-AGGGTGGG			Likely benign (Apr 01, 2023)
14-36517098-GAAAA-G			Benign (Aug 16, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NKX2-1	protein_coding	protein_coding	ENST00000354822	3	4753

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.359	0.639	121082	0	4	121086	0.0000165

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.81	149	225	0.661	0.0000101	2550
Missense in Polyphen		60	107.29	0.55922		1204
Synonymous	-0.913	112	100	1.12	0.00000475	822
Loss of Function	2.61	3	13.2	0.227	5.73e-7	130

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000565	0.0000564
Finnish	0.00	0.00
European (Non-Finnish)	0.0000284	0.0000278
Middle Eastern	0.0000565	0.0000564
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor. Crucial in the maintenance of the thyroid differentiation phenotype. May play a role in lung development and surfactant homeostasis. Forms a regulatory loop with GRHL2 that coordinates lung epithelial cell morphogenesis and differentiation. Activates the transcription of GNRHR and plays a role in enhancing the circadian oscillation of its gene expression. Represses the transcription of the circadian transcriptional repressor NR1D1 (By similarity). {ECO:0000250|UniProtKB:P23441, ECO:0000250|UniProtKB:P50220}.
• Disease: DISEASE: Chorea, hereditary benign (BHC) [MIM:118700]: A rare autosomal dominant movement disorder, defined by early onset in childhood, a stable or non-progressive course of chorea, and no mental deterioration. Chorea is characterized by involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. {ECO:0000269|PubMed:11971878, ECO:0000269|PubMed:15955952, ECO:0000269|PubMed:24453141, ECO:0000269|PubMed:26723978}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP) [MIM:610978]: An autosomal dominant disorder that manifests in infancy with neurological disturbances, hypothyroidism, and respiratory problems. It is characterized by movement abnormalities beginning with muscular hypotonia followed by the development of chorea, athetosis, dystonia, ataxia, and dysarthria. {ECO:0000269|PubMed:11854318, ECO:0000269|PubMed:11854319, ECO:0000269|PubMed:15289765, ECO:0000269|PubMed:15955952, ECO:0000269|PubMed:24714694}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thyroid cancer, non-medullary, 1 (NMTC1) [MIM:188550]: A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. {ECO:0000269|PubMed:19176457}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Endoderm Differentiation;Preimplantation Embryo;Tgif disruption of Shh signaling;FOXA2 and FOXA3 transcription factor networks (Consensus)

Recessive Scores

• pRec: 0.523

Haploinsufficiency Scores

• pHI: 0.815
• hipred: Y
• hipred_score: 0.856
• ghis: 0.634

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.928

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nkx2-1
• Phenotype: skeleton 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); digestive/alimentary phenotype; reproductive system 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; 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); neoplasm; respiratory 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; growth/size/body region phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;neuron migration;phospholipid metabolic process;axon guidance;brain development;endoderm development;locomotory behavior;response to hormone;positive regulation of gene expression;negative regulation of epithelial to mesenchymal transition;globus pallidus development;hippocampus development;cerebral cortex cell migration;forebrain dorsal/ventral pattern formation;forebrain neuron fate commitment;cerebral cortex GABAergic interneuron differentiation;pituitary gland development;cell differentiation;lung development;negative regulation of cell migration;negative regulation of transforming growth factor beta receptor signaling pathway;thyroid gland development;forebrain development;developmental induction;Leydig cell differentiation;positive regulation of circadian rhythm;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;rhythmic process;anatomical structure formation involved in morphogenesis;oligodendrocyte differentiation;lung saccule development;epithelial tube branching involved in lung morphogenesis;Clara cell differentiation;type II pneumocyte differentiation
• Cellular component: nucleus;nucleoplasm;transcription factor complex
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;RNA polymerase II distal enhancer sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;RNA polymerase II regulatory region DNA binding;intronic transcription regulatory region sequence-specific DNA binding;DNA binding;DNA-binding transcription factor activity;protein binding;enzyme binding;sequence-specific DNA binding;transcription regulatory region DNA binding;intronic transcription regulatory region DNA binding