NKX2-6

NK2 homeobox 6, the group of NKL subclass homeoboxes and pseudogenes

Basic information

Region (hg38): 8:23701739-23706756

Links

ENSG00000180053 ∙ NCBI:137814 ∙ OMIM:611770 ∙ HGNC:32940 ∙ Uniprot:A6NCS4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• conotruncal heart malformations (Moderate), mode of inheritance: AR
• conotruncal heart malformations (Limited), mode of inheritance: AR
• congenital heart disease (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Persistent truncus arteriosus; Conotruncal heart malformations	AR	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early management	Cardiovascular	15649947

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NKX2-6 gene.

• Conotruncal heart malformations (63 variants)
• not provided (19 variants)
• NKX2-6-related condition (5 variants)
• not specified (4 variants)
• Inborn genetic diseases (4 variants)
• Cerebral palsy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NKX2-6 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				12	3	15
missense			45	5		50
nonsense		1				1
start loss						0
frameshift		2	4			6
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				1	9	10
Total	0	3	50	18	12

Variants in NKX2-6

This is a list of pathogenic ClinVar variants found in the NKX2-6 region.

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

Position	Type	Phenotype	Significance	ClinVar
8-23702248-T-C			Benign (Sep 04, 2018)
8-23702404-A-AG			Benign (Sep 06, 2018)
8-23702462-T-C		Conotruncal heart malformations	Uncertain significance (Oct 20, 2022)
8-23702479-G-T		NKX2-6-related disorder	Uncertain significance (Apr 29, 2023)
8-23702490-G-A		Conotruncal heart malformations	Likely benign (Oct 22, 2017)
8-23702531-C-A		Conotruncal heart malformations	Uncertain significance (Jul 10, 2023)
8-23702556-A-G		Conotruncal heart malformations	Likely benign (Mar 20, 2023)
8-23702571-G-C		Conotruncal heart malformations • NKX2-6-related disorder • not specified	Benign (Jan 31, 2024)
8-23702577-G-A		Conotruncal heart malformations	Likely benign (Aug 28, 2023)
8-23702586-G-A		Conotruncal heart malformations	Likely benign (Mar 17, 2023)
8-23702586-G-C		Conotruncal heart malformations	Likely benign (Jul 31, 2020)
8-23702612-C-T		Conotruncal heart malformations	Uncertain significance (Mar 01, 2022)
8-23702659-G-T		Conotruncal heart malformations	Uncertain significance (Dec 19, 2021)
8-23702664-G-A			Likely benign (May 08, 2018)
8-23702671-G-A		Conotruncal heart malformations	Uncertain significance (Feb 07, 2018)
8-23702684-G-A		Conotruncal heart malformations	Uncertain significance (Dec 30, 2019)
8-23702687-CGGGGCCCAGGCAGGGCTTGCCATCGCGCACCA-C			Uncertain significance (Mar 01, 2022)
8-23702708-C-A		Conotruncal heart malformations	Uncertain significance (Dec 30, 2019)
8-23702713-C-T		Conotruncal heart malformations • NKX2-6-related disorder	Uncertain significance (Oct 03, 2023)
8-23702725-G-C		Conotruncal heart malformations	Uncertain significance (Nov 20, 2023)
8-23702732-C-A		Conotruncal heart malformations	Uncertain significance (Jan 01, 2020)
8-23702737-C-T		Conotruncal heart malformations	Uncertain significance (Nov 14, 2019)
8-23702743-G-A		Conotruncal heart malformations	Uncertain significance (Jan 26, 2024)
8-23702764-A-G		Conotruncal heart malformations	Uncertain significance (Oct 27, 2022)
8-23702768-C-T		Inborn genetic diseases	Uncertain significance (Jan 26, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NKX2-6	protein_coding	protein_coding	ENST00000325017	2	4148

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0189	0.906	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.264	165	175	0.944	0.00000800	1846
Missense in Polyphen		44	47.282	0.93058		503
Synonymous	1.72	63	83.0	0.759	0.00000384	684
Loss of Function	1.51	4	8.84	0.453	4.08e-7	82

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	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: Acts as a transcriptional activator (PubMed:15649947). In conjunction with NKX2-5, may play a role in both pharyngeal and cardiac embryonic development. {ECO:0000250|UniProtKB:P43688, ECO:0000269|PubMed:15649947}.
• Disease: 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:15649947, ECO:0000269|PubMed:24421281, ECO:0000269|PubMed:25195019, ECO:0000269|PubMed:25380965}. Note=The disease may be caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.106

Haploinsufficiency Scores

• pHI: 0.0568
• hipred: N
• hipred_score: 0.220
• ghis: 0.465

Essentials

• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.490

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nkx2-6
• Phenotype: respiratory system phenotype; embryo phenotype; normal 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); 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); cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: nkx2.7
• Affected structure: ventricular myocardium
• Phenotype tag: abnormal
• Phenotype quality: shortened

Gene ontology

• Biological process: positive regulation of cell population proliferation;hypothalamus development;cell differentiation;embryonic heart tube development;negative regulation of apoptotic process;tongue development;positive regulation of transcription by RNA polymerase II;digestive tract development;atrial cardiac muscle cell development;ventricular cardiac muscle cell development;pharyngeal system development;pericardium development
• Cellular component: nucleus
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;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 transcription factor activity;sequence-specific DNA binding