NCKAP1L

NCK associated protein 1 like

Basic information

Region (hg38): 12:54497752-54548243

Previous symbols: [ "HEM1" ]

Links

ENSG00000123338 ∙ NCBI:3071 ∙ OMIM:141180 ∙ HGNC:4862 ∙ Uniprot:P55160 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• immunodeficiency 72 with autoinflammation (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 72 with autoinflammation and lymphoproliferation	AR	Allergy/Immunology/Infectious	The condition can involve early-onset and severe infections, as well as other immunologic manifestations, and awareness may allow early and aggressive treatment of infections; Medical management of autoimmune disease (with immunomodulatory agents) has been described as beneficial in some individuals	Allergy/Immunology/Infectious	32647003

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NCKAP1L gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NCKAP1L 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				101	11	112
missense		4	95	5	2	106
nonsense			3			3
start loss		1				1
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)		1	3		1	5
splice region			9	24	4	37
non coding			1	70	15	86
Total	0	6	103	176	29

Variants in NCKAP1L

This is a list of pathogenic ClinVar variants found in the NCKAP1L region.

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

Position	Type	Phenotype	Significance	ClinVar
12-54497791-T-C		Immunodeficiency 72 with autoinflammation	Likely pathogenic (-)
12-54497801-A-C			Likely benign (Aug 25, 2023)
12-54497807-T-C			Likely benign (Aug 25, 2023)
12-54497847-G-T		not specified	Uncertain significance (May 12, 2024)
12-54497850-C-T		not specified	Uncertain significance (Jan 06, 2023)
12-54497852-C-T			Likely benign (Dec 09, 2023)
12-54497872-G-A			Uncertain significance (Mar 04, 2022)
12-54497879-T-C			Likely benign (Nov 27, 2023)
12-54497887-A-G		not specified	Uncertain significance (May 29, 2022)
12-54497899-T-C			Likely benign (May 09, 2022)
12-54497906-T-TG			Likely benign (Nov 24, 2023)
12-54497907-G-A			Likely benign (Jan 01, 2024)
12-54497908-G-T			Likely benign (Aug 29, 2023)
12-54499347-C-T			Likely benign (Jan 12, 2023)
12-54499351-G-A			Likely benign (May 29, 2023)
12-54499362-C-T			Uncertain significance (May 28, 2022)
12-54499410-C-T		not specified	Uncertain significance (Sep 17, 2022)
12-54499417-C-A			Likely benign (Aug 28, 2022)
12-54499424-A-G			Likely benign (Dec 23, 2023)
12-54499448-G-C		NCKAP1L-related disorder	Benign (Jan 20, 2024)
12-54499455-G-A		not specified	Uncertain significance (Dec 21, 2022)
12-54499463-A-G		not specified	Uncertain significance (Dec 21, 2023)
12-54499468-G-A			Uncertain significance (Dec 18, 2023)
12-54499483-C-G			Likely benign (Dec 01, 2022)
12-54500536-C-T			Likely benign (Dec 13, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NCKAP1L	protein_coding	protein_coding	ENST00000293373	31	46232

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.855	0.145	125707	0	41	125748	0.000163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.48	456	631	0.723	0.0000341	7438
Missense in Polyphen		134	217.54	0.61597		2504
Synonymous	0.0300	229	230	0.997	0.0000114	2171
Loss of Function	5.88	13	63.6	0.204	0.00000336	730

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.00	0.00
Finnish	0.000370	0.000370
European (Non-Finnish)	0.000229	0.000229
Middle Eastern	0.00	0.00
South Asian	0.000131	0.000131
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Essential hematopoietic-specific regulator of the actin cytoskeleton (Probable). Controls lymphocyte development, activation, proliferation and homeostasis, erythrocyte membrane stability, as well as phagocytosis and migration by neutrophils and macrophages (PubMed:16417406, PubMed:17696648). Component of the WAVE2 complex which signals downstream of RAC to stimulate F- actin polymerization. Required for stabilization and/or translation of the WAVE2 complex proteins in hematopoietic cells (By similarity). Exhibits complex cycles of activation and inhibition to generate waves of propagating the assembly with actin (PubMed:16417406). Also involved in mechanisms WAVE- independent to regulate myosin and actin polymerization during neutrophil chemotaxis (PubMed:17696648). {ECO:0000250|UniProtKB:Q8K1X4, ECO:0000269|PubMed:16417406, ECO:0000269|PubMed:17696648, ECO:0000303|PubMed:20969869}.
• Pathway: Regulation of actin cytoskeleton - Homo sapiens (human);Hematopoietic Stem Cell Differentiation;Microglia Pathogen Phagocytosis Pathway;TYROBP Causal Network;Neutrophil degranulation;Signal Transduction;VEGFA-VEGFR2 Pathway;Fcgamma receptor (FCGR) dependent phagocytosis;Innate Immune System;Immune System;RHO GTPases Activate WASPs and WAVEs;RHO GTPase Effectors;Signaling by Rho GTPases;Regulation of actin dynamics for phagocytic cup formation;Signaling by VEGF;Signaling by Receptor Tyrosine Kinases (Consensus)

Recessive Scores

• pRec: 0.105

Intolerance Scores

• loftool: 0.664
• rvis_EVS: -0.46
• rvis_percentile_EVS: 23.69

Haploinsufficiency Scores

• pHI: 0.462
• hipred: Y
• hipred_score: 0.563
• ghis: 0.538

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.909

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nckap1l
• Phenotype: endocrine/exocrine gland phenotype; growth/size/body region phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; respiratory system phenotype; liver/biliary system phenotype; reproductive system phenotype; hematopoietic system 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); renal/urinary system phenotype

Gene ontology

• Biological process: cell morphogenesis;B cell homeostasis;myeloid cell homeostasis;chemotaxis;cell migration;maintenance of cell polarity;cell projection assembly;neutrophil chemotaxis;positive regulation of actin filament polymerization;cortical actin cytoskeleton organization;positive regulation of B cell proliferation;activation of protein kinase activity;negative regulation of interleukin-17 production;negative regulation of interleukin-6 production;positive regulation of cell adhesion mediated by integrin;erythrocyte homeostasis;negative regulation of myosin-light-chain-phosphatase activity;Fc-gamma receptor signaling pathway involved in phagocytosis;positive regulation of T cell proliferation;positive regulation of phosphorylation;response to drug;T cell homeostasis;negative regulation of apoptotic process;neutrophil degranulation;positive regulation of CD4-positive, alpha-beta T cell differentiation;positive regulation of CD8-positive, alpha-beta T cell differentiation;positive regulation of GTPase activity;positive regulation of B cell differentiation;positive regulation of gamma-delta T cell differentiation;positive regulation of lymphocyte differentiation;positive regulation of erythrocyte differentiation;vascular endothelial growth factor receptor signaling pathway;neuron projection morphogenesis;erythrocyte development;B cell receptor signaling pathway;positive regulation of phagocytosis, engulfment;protein-containing complex assembly;actin polymerization-dependent cell motility;positive regulation of neutrophil chemotaxis
• Cellular component: cytosol;plasma membrane;integral component of plasma membrane;membrane;secretory granule membrane;SCAR complex;extracellular exosome;ficolin-1-rich granule membrane
• Molecular function: GTPase activator activity;protein binding;protein kinase activator activity;protein-containing complex binding;Rac GTPase binding