NKX2-5

Chr 5

NK2 homeobox 5

Also known as: CHNG5, CSX, CSX1, HLHS2, NKX2.5, NKX2E, NKX4-1, VSD3

NCBI Gene: 1482 ENSG00000183072 UniProt: P52952

This gene encodes a homeobox transcription factor required for heart and spleen development that binds to specific DNA motifs and cooperates with other transcription factors like GATA4. Mutations cause various congenital heart malformations including atrial septal defects, tetralogy of Fallot, hypoplastic left heart syndrome, and ventricular septal defects, as well as congenital nongoitrous hypothyroidism. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants (pLI 0.95).

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.33

Clinical Summary— NKX2-5

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Gene-Disease Validity (ClinGen)

NKX2.5-related congenital, conduction and myopathic heart disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

134 unique Pathogenic / Likely Pathogenic· 380 VUS of 826 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NKX2-5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.945

Z-score 2.81

OE 0.00 (0.00–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.20Z-score

OE missense 0.96 (0.85–1.09)

178 obs / 185.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.33)

0≤0.351.4

Missense OE?0.96 (0.85–1.09)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 0 / 9.2Missense obs/exp: 178 / 185.6Syn Z: -0.02

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedNKX2-5-related dilated cardiomyopathyOTHERAD

definitiveNKX2-5-related congenital hypothyroidism non-goitrousDNAD

definitiveNKX2-5-related tetralogy of FallotOTHERAD

definitiveNKX2-5-related atrial septal defect with atrioventricular conduction defectsLOFAD

This gene — mechanism propensity

0.4586th %ile

GOF

0.2696th %ile

LOF

0.81top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 72% of P/LP variants are LoF · LOEUF 0.33 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNNKX2-5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a domin1

GOFOur study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gain-of-function in congenital heart disease.2

LOFTwo are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

826 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic95

Likely Pathogenic39

VUS380

Likely Benign249

Benign16

Conflicting45

Pathogenic

Likely Pathogenic

380

VUS

249

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	71	17	7	0	95
Likely Pathogenic	26	11	2	0	39
VUS	7	359	13	1	380
Likely Benign	0	14	28	207	249
Benign	0	0	13	3	16
Conflicting	—				45
Total	104	401	63	211	824

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

20 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap NKX2-5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →