NKX2-6

protein-coding

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

Gene summary

This gene encodes a homeobox-containing protein that belongs to the NK-2 homeobox family. This protein is a vertebrate homolog of Drosophila homeobox-containing protein called 'tinman', which has been shown to be essential for development of the heart-like dorsal vessel. In conjunction with related gene, NKX2-5, this gene may play a role in both pharyngeal and cardiac embryonic development. Mutations in this gene are associated with persistent truncus arteriosus.[provided by RefSeq, Aug 2011]

MANE transcript

NM_001136271.3

Inheritance

ClinVar variants

P:5U:80B:40

Top phenotype

Persistent truncus arteriosus; Conotruncal heart malformations

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr8:23,701,740-23,706,756

External References & Databases

Ensembl (ENSG00000180053)

Transcript & Mutation Effects

hg38 • Region Span ~5.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

conotruncal heart malformationsLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0016581

Submitter: Labcorp Genetics (formerly Invitae)

conotruncal heart malformationsMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0016581

Submitter: Ambry Genetics

congenital heart diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005453

Submitter: ClinGen

*NKX2-6* was first reported in relation to autosomal recessive congenital heart disease in 2005 (Heathcote et al. 2005; PMID: 15649947). Four variants (1 missense variant, 1 nonsense variant, and 2 frameshift variants) that have been reported in three probands in three publications (PMIDs:15649947,32198970,24421281) are included in this curation. 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 January 2nd, 2024 (SOP Version 10).

congenital heart diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0005453

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Persistent truncus arteriosus; Conotruncal heart malformationsAR

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 15649947

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NKX2-6 variants in ClinVar

7 Conditions Cataloged

Conotruncal heart malformationsTotal: 92

Inborn genetic diseasesTotal: 20

not providedTotal: 17

NKX2-6-related disorderTotal: 15

not specifiedTotal: 9

Cerebral palsyTotal: 1

Persistent truncus arteriosusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001136271.3. 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				31 clinvar	2 clinvar	33
missense		1 clinvar	74 clinvar	7 clinvar		82
nonsense		1 clinvar	1 clinvar			2
start loss			1 clinvar			1
frameshift		3 clinvar	4 clinvar			7
splice donor/acceptor (+/-2bp)						0
Total	0	5	80	38	2	125

Highest pathogenic variant AF is 0.000038620077

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001136271.3	RefSeq	NP_001129743.2	2	MANE Select
ENST00000325017.4	Ensembl	ENSP00000320089.3	2	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nkx2.7	Danio rerio	Structure: ventricular myocardium Quality: shortened abnormal

Gene / Model

Organism

Observed Phenotype

nkx2.7

Danio rerio

Structure: ventricular myocardium

Quality: shortened

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of cell population proliferation
hypothalamus development
cell differentiation
embryonic heart tube development
negative regulation of apoptotic process

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000325017
Coding exons: 2
Length: 4148
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.264	165	175	0.944	0.00000800	1846
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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

Essentials

Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.490

Gene Damage Prediction

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