NALCN

protein-coding

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

Gene summary

This gene encodes a voltage-independent, nonselective cation channel which belongs to a family of voltage-gated sodium and calcium channels that regulates the resting membrane potential and excitability of neurons. This family is expressed throughout the nervous system and conducts a persistent sodium leak current that contributes to tonic neuronal excitability. The encoded protein forms a channelosome complex that includes G-protein-coupled receptors, UNC-79, UNC-80, NCA localization factor-1, and src family tyrosine kinases. Naturally occurring mutations in this gene are associated with infantile neuroaxonal dystrophy, infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) syndrome, and congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD) syndrome. A knockout of the orthologous gene in mice results in paralysis with a severely disrupted respiratory rhythm, and lethality within 24 hours after birth. [provided by RefSeq, Apr 2017]

Previous symbols:

VGCNL1

MANE transcript

NM_052867.4

Inheritance

AD, AR

ClinVar variants

P:197U:573B:247

Top phenotype

Congenital contractures of the limbs and face, hypotonia, and developmental delay; Hypotonia, infantile, with psychomotor retardation and characteristic facies 1

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr13:101,053,776-101,416,508

External References & Databases

Ensembl (ENSG00000102452)

Transcript & Mutation Effects

hg38 • Region Span ~362.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Sheldon-hall syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011128

Submitter: Orphanet

digitotalar dysmorphismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015240

Submitter: Orphanet

congenital contractures of the limbs and face, hypotonia, and developmental delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014556

Submitter: PanelApp Australia

Freeman-Sheldon syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008675

Submitter: Orphanet

temporal lobe epilepsyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005115

Submitter: G2P

congenital contractures of the limbs and face, hypotonia, and developmental delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014556

Submitter: Labcorp Genetics (formerly Invitae)

hypotonia, infantile, with psychomotor retardation and characteristic facies 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024567

Submitter: G2P

hypotonia, infantile, with psychomotor retardation and characteristic facies 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024567

Submitter: Labcorp Genetics (formerly Invitae)

hypotonia, infantile, with psychomotor retardation and characteristic faciesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014176

Submitter: PanelApp Australia

congenital contractures of the limbs and face, hypotonia, and developmental delayDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014556

Submitter: G2P

Clinical Genomic Database (CGD)

Congenital contractures of the limbs and face, hypotonia, and developmental delay; Hypotonia, infantile, with psychomotor retardation and characteristic facies 1AD/AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Refs: 12558119; 23749988; 25683120

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NALCN variants in ClinVar

23 Conditions Cataloged

not providedTotal: 1044

Inborn genetic diseasesTotal: 187

Congenital contractures of the limbs and face, hypotonia, and developmental delayTotal: 144

not specifiedTotal: 101

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1Total: 91

NALCN-related disorderTotal: 74

Intellectual disabilityTotal: 3

See casesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_052867.4. 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	1 clinvar		19 clinvar	216 clinvar	6 clinvar	242
missense	22 clinvar	74 clinvar	545 clinvar	24 clinvar	1 clinvar	666
nonsense	24 clinvar	13 clinvar	2 clinvar			39
start loss						0
frameshift	24 clinvar	19 clinvar	3 clinvar			46
splice donor/acceptor (+/-2bp)	2 clinvar	18 clinvar	4 clinvar			24
Total	73	124	573	240	7	1017

Highest pathogenic variant AF is 0.000025403104

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_052867.4	RefSeq	NP_443099.1	43	MANE Select
ENST00000251127.11	Ensembl	ENSP00000251127.6	43	MANE Select
NM_001350748.2	RefSeq	NP_001337677.1	44	Standard
NM_001350749.2	RefSeq	NP_001337678.1	43	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

ion transmembrane transport
regulation of ion transmembrane transport
sodium ion transmembrane transport
regulation of resting membrane potential
calcium ion transmembrane transport

Molecular Function

voltage-gated ion channel activity
cation channel activity
sodium channel activity
protein binding
leak channel activity

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000251127
Coding exons: 43
Length: 362714
Individuals with no LoFs: 125661
Homozygous LoFs: 0
Heterozygous LoFs: 87
Defined: 125748
p: 0.000346

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.96	563	1.01e+3	0.560	0.0000581	11493
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00033	0.00033	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00039	0.00039	rare
South Asian	0.00043	0.00042	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.0947
RVIS EVS: -1.61
RVIS percentile EVS: 2.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.236

Gene Damage Prediction

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