NFATC2

protein-coding

nuclear factor of activated T cells 2, the group of Nuclear factors of activated T-cells |IPT domain containing|MicroRNA protein coding host genes

Gene summary

This gene is a member of the nuclear factor of activated T cells (NFAT) family. The product of this gene is a DNA-binding protein with a REL-homology region (RHR) and an NFAT-homology region (NHR). This protein is present in the cytosol and only translocates to the nucleus upon T cell receptor (TCR) stimulation, where it becomes a member of the nuclear factors of activated T cells transcription complex. This complex plays a central role in inducing gene transcription during the immune response. Alternate transcriptional splice variants encoding different isoforms have been characterized. [provided by RefSeq, Apr 2012]

MANE transcript

NM_012340.5

Inheritance

AD, AR

ClinVar variants

P:1U:131B:13

Top phenotype

Joint contractures, osteochondromas, and B-cell lymphoma

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr20:51,386,957-51,562,831

External References & Databases

Ensembl (ENSG00000101096)

Transcript & Mutation Effects

hg38 • Region Span ~175.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*NFATC2* was reported in relation to autosomal dominant congenital heart disease in 2014 (Briand-Suleau, A et al., PMID: 24486774). No genetic evidence linking *NFATC2* was identified in the literature or elsewhere. Genetic cases of *NFATC2* were seen to be a player in the congenital heart defects in patients with the 20q13.2 duplication along with *SALL4* (PMID: 24486774). Functional alteration experimental evidence analyzed the mRNA levels in candidate CHD genes in the right ventricular myocardium of TOF cases and normal controls. Evidence found that higher methylation of *NFATC2* might constitute a CpG island methylator phenotype for TOF disease (PMID: 24479926). In summary, the evidence supporting the relationship between *NFATC2* and autosomal dominant congenital heart disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *NFATC2* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date March 11th, 2024 (SOP Version 10).

joint contractures, osteochondromas, and B-cell lymphomaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0859369

Submitter: Labcorp Genetics (formerly Invitae)

lymphoproliferative syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0016537

Submitter: PanelApp Australia

joint contractures, osteochondromas, and B-cell lymphomaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859369

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Joint contractures, osteochondromas, and B-cell lymphomaAR

Manifestation: Musculoskeletal; Oncologic

Intervention: Oncologic

Rationale: The condition can involve risk of hematologic malignancy, and awareness may allow early identification and management

Refs: 35789258

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NFATC2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 126

not providedTotal: 14

Joint contractures, osteochondromas, and B-cell lymphomaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012340.5. 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			2 clinvar	4 clinvar	3 clinvar	9
missense			128 clinvar	4 clinvar	2 clinvar	134
nonsense						0
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	1	0	131	8	5	145

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012340.5	RefSeq	NP_036472.2	10	MANE Select
ENST00000371564.8	Ensembl	ENSP00000360619.3	10	MANE Select
NM_001136021.3	RefSeq	NP_001129493.1	10	Standard
NM_001258292.2	RefSeq	NP_001245221.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxytocin signaling pathway - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
B cell receptor signaling pathway - Homo sapiens (human)
Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
VEGF signaling pathway - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
cytokine production
regulation of transcription, DNA-templated
cellular response to DNA damage stimulus
myotube cell development

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
transcription factor complex
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396009
Coding exons: 10
Length: 175877
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.64	485	598	0.811	0.0000395	5938
Missense (PolyPhen)		120	215.48	0.55689		2116
Synonymous	-0.451	287	277	1.03	0.0000215	1947
Loss of Function	5.53	3	41.4	0.0725	0.00000255	393

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	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2, IL-3, IL-4, TNF-alpha or GM-CSF. Promotes invasive migration through the activation of GPC6 expression and WNT5A signaling pathway. {ECO:0000269|PubMed:15790681, ECO:0000269|PubMed:21871017}.;

Recessive Scores

pRec: 0.429

Intolerance Scores

LoFtool: 0.238
RVIS EVS: -1.57
RVIS percentile EVS: 3.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.672

Gene Damage Prediction

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