UNC80

protein-coding

unc-80 homolog, NALCN channel complex subunit

Gene summary

The protein encoded by this gene is a component of a voltage-independent 'leak' ion-channel complex, in which it performs essential functions, such as serving as a bridge between two other components (sodium leak channel non-selective and UNC79) and as a scaffold for Src kinases. Leak channels play an importnat role in establishment and maintenance of resting membrane potentials in neurons. Mutations in this gene are associated with congenital infantile encephalopathy, intellectual disability and growth issues. [provided by RefSeq, Aug 2016]

Previous symbols:

C2orf21

MANE transcript

NM_001371986.1

Inheritance

ClinVar variants

P:153U:1035B:821

Top phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr2:209,771,569-209,999,300

External References & Databases

Ensembl (ENSG00000144406)

Transcript & Mutation Effects

hg38 • Region Span ~227.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypotonia, infantile, with psychomotor retardation and characteristic facies 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014777

Submitter: Illumina

The UNC80 gene is located on chromosome 2 at 2q34 and encodes unc-80 homolog, NALCN channel complex subunit, which is a component of a sodium channel complex that regulates channel activity. UNC80 was first reported in relation to autosomal recessive UNC80-related hypotonia, infantile, with psychomotor retardation and characteristic facies, in 2016 (26708753: Shamseldin et al., 2016; 26708751: Stray-Pedersen et al. 2016). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 unique variants reported in eight cases from four publications (26708753: Shamseldin et al. 2016; 26708751: Stray-Pedersen et al. 2016; 30167850: Bramswig et al. 2018; 30771478: Kuptanon et al. 2019) One variant was a missense with experimental evidence of a loss-of-function effect; the remainder were predicted null variants. No segregation evidence was scored, but variants in this gene co-segregated with disease in three additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Homozygous loss of function is implicated as the mechanism of disease. This gene-disease relationship is supported by knockout/knockdown models in C. Elegans and Drosophila, including rescue, as well as demonstration of physical interaction with another gene product associated with a similar phenotype (18336069: Yeh et al. 2008; 24223770: Lear et al. 2013). In summary, UNC80 is definitively associated with autosomal recessive UNC80-related hypotonia, infantile, with psychomotor retardation and characteristic facies. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

hypotonia, infantile, with psychomotor retardation and characteristic facies 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014777

Submitter: Labcorp Genetics (formerly Invitae)

hypotonia, infantile, with psychomotor retardation and characteristic faciesSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014176

Submitter: Orphanet

hypotonia, infantile, with psychomotor retardation and characteristic facies 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014777

Submitter: PanelApp Australia

hypotonia, infantile, with psychomotor retardation and characteristic facies 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014777

Submitter: ClinGen

The UNC80 gene is located on chromosome 2 at 2q34 and encodes unc-80 homolog, NALCN channel complex subunit, which is a component of a sodium channel complex that regulates channel activity. UNC80 was first reported in relation to autosomal recessive hypotonia, infantile, with psychomotor retardation and characteristic facies 2 in 2016 (Shamseldin et al., 26708753; Stray-Pedersen et al., 26708751). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 unique variants reported in eight cases from four publications (26708753: Shamseldin et al. 2016; 26708751: Stray-Pedersen et al. 2016; 30167850: Bramswig et al. 2018; 30771478: Kuptanon et al. 2019). One variant was a missense with experimental evidence of a loss-of-function effect; the remainder were predicted null variants. No segregation evidence was scored, but variants in this gene co-segregated with disease in three additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Biallelic loss of function is implicated as the mechanism of disease. This gene-disease relationship is supported by knockout/knockdown models in C. elegans and Drosophila, including rescue in C.elegans with the model organism gene, as well as demonstration of an effect on trafficking of the UNC80 protein and sodium NALCN-dependent sodium leak current (18336069: Yeh et al. 2008; 24223770: Lear et al. 2013; 32620897: Wie et al. 2020). In summary, UNC80 is definitively associated with autosomal recessive hypotonia, infantile, with psychomotor retardation and characteristic facies 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 4Nov2020 (SOP Version 7).

hypotonia, infantile, with psychomotor retardation and characteristic facies 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014777

Submitter: G2P

Clinical Genomic Database (CGD)

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2AR

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: 26862157; 26708751; 26708753

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UNC80 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 2343

Inborn genetic diseasesTotal: 357

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2Total: 177

UNC80-related disorderTotal: 84

not specifiedTotal: 36

Intellectual disabilityTotal: 4

See casesTotal: 3

EncephalopathyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001371986.1. 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			20 clinvar	749 clinvar	21 clinvar	790
missense		8 clinvar	1004 clinvar	42 clinvar	9 clinvar	1063
nonsense	46 clinvar	13 clinvar	1 clinvar			60
start loss			1 clinvar			1
frameshift	31 clinvar	11 clinvar	5 clinvar			47
splice donor/acceptor (+/-2bp)	4 clinvar	40 clinvar	4 clinvar			48
Total	81	72	1035	791	30	2009

Highest pathogenic variant AF is 0.00004956869

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001371986.1	RefSeq	NP_001358915.1	65	MANE Select
ENST00000673920.1	Ensembl	ENSP00000501211.1	65	MANE Select
NM_032504.2	RefSeq	NP_115893.1	64	Standard
NM_182587.4	RefSeq	NP_872393.3	63	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

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000439458
Coding exons: 64
Length: 227308
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125745
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.53	1089	1.74e+3	0.627	0.0000996	21316
Missense (PolyPhen)		591	1021.7	0.57846		12466
Synonymous	3.79	539	663	0.813	0.0000382	6422
Loss of Function	9.12	39	166	0.235	0.0000100	1901

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the NALCN sodium channel complex, required for channel regulation. This complex is a cation channel activated by neuropeptides substance P, neurotensin, and extracellular calcium that regulates neuronal excitability by controlling the sizes of NALCN-dependent sodium-leak current. UNC80 is essential for NALCN sensitivity to extracellular calcium. {ECO:0000250|UniProtKB:Q8BLN6}.;
Disease: DISEASE: Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (IHPRF2) [MIM:616801]: An autosomal recessive, neurodegenerative disease characterized by severe truncal hypotonia since birth or early infancy, progressive peripheral spasticity, and profound psychomotor developmental delay. Some patients may have seizures. {ECO:0000269|PubMed:26545877, ECO:0000269|PubMed:26708751, ECO:0000269|PubMed:26708753}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.640
RVIS EVS: 0.99
RVIS percentile EVS: 90.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.231

Gene Damage Prediction

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