NALCN

sodium leak channel, non-selective, the group of Sodium leak channels, non selective

Basic information

Region (hg38): 13:101053775-101416508

Previous symbols: [ "VGCNL1" ]

Links

ENSG00000102452 ∙ NCBI:259232 ∙ OMIM:611549 ∙ HGNC:19082 ∙ Uniprot:Q8IZF0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital contractures of the limbs and face, hypotonia, and developmental delay (Definitive), mode of inheritance: AD
• hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (Definitive), mode of inheritance: AR
• digitotalar dysmorphism (Supportive), mode of inheritance: AD
• Sheldon-hall syndrome (Supportive), mode of inheritance: AD
• Freeman-Sheldon syndrome (Supportive), mode of inheritance: AD
• hypotonia, infantile, with psychomotor retardation and characteristic facies (Supportive), mode of inheritance: AR
• hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (Strong), mode of inheritance: AR
• congenital contractures of the limbs and face, hypotonia, and developmental delay (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital contractures of the limbs and face, hypotonia, and developmental delay; Hypotonia, infantile, with psychomotor retardation and characteristic facies 1	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Musculoskeletal; Neurologic	12558119; 23749988; 25683120

ClinVar

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

• not provided (676 variants)
• Inborn genetic diseases (52 variants)
• Congenital contractures of the limbs and face, hypotonia, and developmental delay (47 variants)
• Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (36 variants)
• not specified (26 variants)
• Hypotonia, infantile, with psychomotor retardation and characteristic facies 1;Congenital contractures of the limbs and face, hypotonia, and developmental delay (10 variants)
• Congenital contractures of the limbs and face, hypotonia, and developmental delay;Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (5 variants)
• NALCN-related condition (5 variants)
• Arthrogryposis multiplex congenita;Fetal akinesia deformation sequence 1 (3 variants)
• See cases (3 variants)
• Abnormality of the nervous system (3 variants)
• Intellectual disability (2 variants)
• NALCN-related disorders (2 variants)
• Strabismus;Intellectual disability, severe;Cachexia;Abnormal pattern of respiration;Seizure (1 variants)
• Developmental disorder (1 variants)
• Neurodevelopmental disorder (1 variants)
• Autism spectrum disorder (1 variants)
• Intellectual disability with episodic ataxia and congenital arthrogryposis (1 variants)
• Hypotonia, infantile, with psychomotor retardation and characteristic facies (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NALCN 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			3	89	11	103
missense	9	33	253	7	2	304
nonsense	12	4	1			17
start loss						0
frameshift	12	12				24
inframe indel			3			3
splice donor/acceptor (+/-2bp)	3	8	3			14
splice region	1	1	15	27	2	46
non coding			7	109	123	239
Total	36	57	270	205	136

Highest pathogenic variant AF is 0.0000197

Variants in NALCN

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

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

Position	Type	Phenotype	Significance	ClinVar
13-101055303-C-G		Congenital contractures of the limbs and face, hypotonia, and developmental delay	Uncertain significance (May 04, 2018)
13-101055309-G-A			Uncertain significance (May 08, 2023)
13-101055318-C-T			Uncertain significance (Mar 18, 2022)
13-101055324-C-T		Congenital contractures of the limbs and face, hypotonia, and developmental delay	Uncertain significance (Nov 25, 2019)
13-101055325-G-A			Likely benign (Sep 28, 2022)
13-101055328-G-C		Inborn genetic diseases	Uncertain significance (Jan 22, 2024)
13-101055347-C-T			Uncertain significance (May 14, 2022)
13-101055348-G-A		Inborn genetic diseases	Uncertain significance (Mar 30, 2023)
13-101055348-G-C		Congenital contractures of the limbs and face, hypotonia, and developmental delay	Uncertain significance (-)
13-101055356-C-T			Uncertain significance (Sep 01, 2020)
13-101055374-C-T		Hypotonia, infantile, with psychomotor retardation and characteristic facies 1;Congenital contractures of the limbs and face, hypotonia, and developmental delay • Inborn genetic diseases	Uncertain significance (Aug 07, 2023)
13-101055385-C-T		NALCN-related disorder	Conflicting classifications of pathogenicity (Feb 01, 2024)
13-101055386-G-A		Inborn genetic diseases	Uncertain significance (Oct 14, 2020)
13-101055387-C-T			Uncertain significance (May 22, 2023)
13-101055399-G-T			Uncertain significance (Jan 12, 2024)
13-101055414-C-T			Conflicting classifications of pathogenicity (Aug 17, 2023)
13-101055418-A-G			Likely benign (Jul 11, 2018)
13-101055425-A-G		not specified	Uncertain significance (Dec 19, 2023)
13-101055432-T-C			Uncertain significance (Feb 21, 2023)
13-101055432-T-G			Uncertain significance (Jun 30, 2022)
13-101055433-C-T			Likely benign (May 08, 2023)
13-101055434-C-T			Uncertain significance (Jan 27, 2020)
13-101055435-T-G			Likely benign (Jan 08, 2024)
13-101055446-C-T			Uncertain significance (Apr 20, 2023)
13-101055447-G-A			Uncertain significance (May 22, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NALCN	protein_coding	protein_coding	ENST00000251127	43	362714

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.52e-14	1.00	125661	0	87	125748	0.000346

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.96	563	1.01e+3	0.560	0.0000581	11493
Missense in Polyphen		144	366.01	0.39343		4318
Synonymous	0.131	366	369	0.991	0.0000230	3252
Loss of Function	5.59	41	102	0.402	0.00000538	1146

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000480	0.000478
Ashkenazi Jewish	0.000299	0.000298
East Asian	0.000332	0.000326
Finnish	0.000231	0.000231
European (Non-Finnish)	0.000390	0.000387
Middle Eastern	0.000332	0.000326
South Asian	0.000431	0.000425
Other	0.000660	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Voltage-independent, cation-nonselective channel which is permeable to sodium, potassium and calcium ions. Regulates the resting membrane potential and controls neuronal excitability (PubMed:17448995). Neuropeptides such as neurotensin and substance P (SP) stimulate the firing of action potentials by activating NALCN through a SRC family kinases-dependent pathway. In addition to its baseline activity, NALCN activity is enhanced/modulated by several GPCRs. Required for normal respiratory rhythm and neonatal survival. Involved in systemic osmoregulation by controlling the serum sodium concentration. NALCN is partly responsible for the substance P-induced depolarization and regulation of the intestinal pace-making activity in the interstitial cells of Cajal. Plays a critical role in both maintenance of spontaneous firing of substantia nigra pars reticulata (SNr) neurons and physiological modulation of SNr neuron excitability (By similarity). {ECO:0000250|UniProtKB:Q8BXR5, ECO:0000269|PubMed:17448995}.
• Disease: DISEASE: Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (IHPRF1) [MIM:615419]: A neurodegenerative disease characterized by variable degrees of hypotonia, speech impairment, intellectual disability, pyramidal signs, subtle facial dysmorphism, and chronic constipation. Some patients manifest neuroaxonal dystrophy, optic atrophy, unmyelinated axons and spheroid bodies in tissue biopsies. {ECO:0000269|PubMed:23749988, ECO:0000269|PubMed:24075186}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) [MIM:616266]: A disease characterized by congenital contractures of the limbs and face, resulting in characteristic facial features, abnormal tone, most commonly manifested as hypotonia, and variable degrees of developmental delay. {ECO:0000269|PubMed:25683120}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Stimuli-sensing channels;Ion channel transport;Transport of small molecules (Consensus)

Recessive Scores

• pRec: 0.103

Intolerance Scores

• loftool: 0.0947
• rvis_EVS: -1.61
• rvis_percentile_EVS: 2.98

Haploinsufficiency Scores

• pHI: 0.431
• hipred: Y
• hipred_score: 0.771
• ghis: 0.591

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.236

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nalcn
• Phenotype: homeostasis/metabolism 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); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: ion transmembrane transport;regulation of ion transmembrane transport;sodium ion transmembrane transport;regulation of resting membrane potential;calcium ion transmembrane transport;potassium ion transmembrane transport
• Cellular component: plasma membrane;integral component of membrane
• Molecular function: voltage-gated ion channel activity;cation channel activity;sodium channel activity;protein binding;leak channel activity