Human Gene Module / Chromosome 2 / UNC80

UNC80unc-80 homolog, NALCN activator

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 12
Rare Variants / Common Variants
22 / 0
Aliases
UNC80, C2orf21,  UNC-80
Associated Syndromes
-
Chromosome Band
2q34
Associated Disorders
ASD
Relevance to Autism

Two de novo variants in the UNC80 gene (one nonsense variant, one missense variant predicted to be damaging) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). An additional de novo loss-of-function (LoF) variant in the UNC80 gene was identified in a proband from the SAGE cohort in Stessman et al., 2017; while no phenotypic information was provided for the SAGE proband in this report, UNC80 was identified as one of eight genes showing a bias for autism versus intellectual disability (two one-tailed binomial tests, P<0.025 for either ASD or ID/DD cases).

Molecular 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. Biallelic variants in UNC80 are responsible for infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; OMIM 616801).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to UNC80 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
3 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) No ASD
4 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No Hypotonia, dystonia
5 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
6 Support - Chen S et al. (2021) Yes Epilepsy/seizures
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - N.Y.) (07/2) No -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Wang J et al. (2023) Yes -
11 Support - Balasar et al. (2023) No -
12 Support - Sanchis-Juan A et al. (2023) No -
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.9760C>A p.Gln3254Lys missense_variant De novo - - 35901164 N.Y.) (07/2)
c.2736C>A p.Cys912Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.7810C>T p.Arg2604Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.1567C>T p.Arg523Ter stop_gained Familial Paternal - 34800434 Chen S et al. (2021)
c.4150G>T p.Glu1384Ter stop_gained Familial Maternal - 28708303 Chrot E , et al. (2017)
c.4069C>T p.Arg1357Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4949C>G p.Thr1650Arg missense_variant Unknown - Simplex 30564305 Guo H , et al. (2018)
c.7670G>T p.Arg2557Ile missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.5151del p.Trp1718GlyfsTer83 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.7122G>C p.Glu2374Asp missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.7595A>C p.Lys2532Thr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.9386G>C p.Gly3129Ala splice_site_variant Familial Maternal - 34800434 Chen S et al. (2021)
c.9510+1G>A - splice_site_variant Unknown Not maternal Simplex 30564305 Guo H , et al. (2018)
c.637G>A p.Val213Ile missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.1441G>A p.Asp481Asn missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.3001C>T p.Arg1001Cys missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4289G>A p.Ser1430Asn missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.9295A>G p.Lys3099Glu missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2399del p.Leu800TrpfsTer19 frameshift_variant Familial Paternal - 28708303 Chrot E , et al. (2017)
c.3831+1G>A p.? splice_site_variant Familial Both parents Multiplex 37524782 Balasar et al. (2023)
c.5378C>T p.Pro1793Leu missense_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
c.7699A>T p.Thr2567Ser missense_variant Familial Both parents Simplex 37541188 Sanchis-Juan A et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo variants in the UNC80 gene (one nonsense variant, one missense variant predicted to be damaging) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). An additional de novo loss-of-function (LoF) variant in the UNC80 gene was identified in a proband from the SAGE cohort in Stessman et al., 2017; while no phenotypic information was provided for the SAGE proband in this report, UNC80 was identified as one of eight genes showing a bias for autism versus intellectual disability (two one-tailed binomial tests, P<0.025 for either ASD or ID/DD cases).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Two de novo variants in the UNC80 gene (one nonsense variant, one missense variant predicted to be damaging) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). An additional de novo loss-of-function (LoF) variant in the UNC80 gene was identified in a proband from the SAGE cohort in Stessman et al., 2017; while no phenotypic information was provided for the SAGE proband in this report, UNC80 was identified as one of eight genes showing a bias for autism versus intellectual disability (two one-tailed binomial tests, P<0.025 for either ASD or ID/DD cases).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo variants in the UNC80 gene (one nonsense variant, one missense variant predicted to be damaging) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). An additional de novo loss-of-function (LoF) variant in the UNC80 gene was identified in a proband from the SAGE cohort in Stessman et al., 2017; while no phenotypic information was provided for the SAGE proband in this report, UNC80 was identified as one of eight genes showing a bias for autism versus intellectual disability (two one-tailed binomial tests, P<0.025 for either ASD or ID/DD cases).

Reports Added
[New Scoring Scheme]
1/1/2019
4
icon
4

Decreased from 4 to 4

Description

Two de novo variants in the UNC80 gene (one nonsense variant, one missense variant predicted to be damaging) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). An additional de novo loss-of-function (LoF) variant in the UNC80 gene was identified in a proband from the SAGE cohort in Stessman et al., 2017; while no phenotypic information was provided for the SAGE proband in this report, UNC80 was identified as one of eight genes showing a bias for autism versus intellectual disability (two one-tailed binomial tests, P<0.025 for either ASD or ID/DD cases).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

Two de novo variants in the UNC80 gene (one nonsense variant, one missense variant predicted to be damaging) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). An additional de novo loss-of-function (LoF) variant in the UNC80 gene was identified in a proband from the SAGE cohort in Stessman et al., 2017; while no phenotypic information was provided for the SAGE proband in this report, UNC80 was identified as one of eight genes showing a bias for autism versus intellectual disability (two one-tailed binomial tests, P<0.025 for either ASD or ID/DD cases).

Reports Added
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
1/1/2017
icon
4

Increased from to 4

Description

Two de novo variants in the UNC80 gene (one nonsense variant, one missense variant predicted to be damaging) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). An additional de novo loss-of-function (LoF) variant in the UNC80 gene was identified in a proband from the SAGE cohort in Stessman et al., 2017; while no phenotypic information was provided for the SAGE proband in this report, UNC80 was identified as one of eight genes showing a bias for autism versus intellectual disability (two one-tailed binomial tests, P<0.025 for either ASD or ID/DD cases).

Krishnan Probability Score

Score 0.49323688553878

Ranking 4227/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.13983911056561

Ranking 7483/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
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