Human Gene Module / Chromosome 14 / PACS2

PACS2phosphofurin acidic cluster sorting protein 2

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
22 / 0
Aliases
PACS2, PACS-2,  PACS1L
Associated Syndromes
-
Chromosome Band
14q32.33
Associated Disorders
ASD
Relevance to Autism

A recurrent de novo missense variant in the PACS2 gene (p.Glu209Lys) was identified in 14 unrelated individuals presenting with neonatal-onset developmental and epileptic encephalopathy (Olson et al., 2018); in addition to recurrent phenotypes such as epilepsy and developmental delay/intellectual disability, three cases in this report presented with autism spectrum disorder/autistic disorder, and six cases presented with stereotypies. A de novo probably damaging missense variant in the PACS2 gene was observed in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

Molecular Function

Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis. In addition, in response to apoptotic inducer, translocates BIB to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated BID, the release of cytochrome c, the activation of caspase-3 thereby causing cell death. May also be involved in ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PACS2 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Primary A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis Olson HE , et al. (2018) No ASD, stereotypies
3 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
4 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) Yes Speech delay
5 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing Bruel AL , et al. (2019) No -
6 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
7 Support - Elena A Sorokina et al. (2021) No -
8 Support - Spataro N et al. (2023) No -
9 Support - Costa CIS et al. (2023) Yes -
10 Support - Balasar et al. (2023) Yes -
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2120-1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.193G>A p.Ala65Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.392C>T p.Thr131Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.415A>C p.Met139Leu missense_variant De novo - - 33004838 Wang T et al. (2020)
c.500C>T p.Ala167Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.574G>C p.Ala192Pro missense_variant De novo - - 33004838 Wang T et al. (2020)
c.2035C>T p.Pro679Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2369C>A p.Thr790Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2369C>T p.Thr790Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2623G>A p.Asp875Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2633T>C p.Phe878Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.625G>A p.Glu209Lys missense_variant De novo - - 29656858 Olson HE , et al. (2018)
c.625G>A p.Glu209Lys missense_variant De novo - - 31231135 Bruel AL , et al. (2019)
c.625G>A p.Glu209Lys missense_variant De novo - - 31036916 Lecoquierre F , et al. (2019)
c.625G>A p.Glu209Lys missense_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.1822C>T p.Arg608Cys missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.1151del p.Pro384LeufsTer55 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.625G>A p.Glu209Lys missense_variant De novo - Simplex 29656858 Olson HE , et al. (2018)
c.566G>A p.Gly189Asp missense_variant De novo - Unknown 31130284 Monies D , et al. (2019)
c.424G>A p.Val142Met missense_variant De novo - Simplex 37280359 Costa CIS et al. (2023)
c.910G>A p.Asp304Asn missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.625G>A p.Glu209Lys missense_variant Unknown Not paternal - 36980980 Spataro N et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A recurrent de novo missense variant in the PACS2 gene (p.Glu209Lys) was identified in 14 unrelated individuals presenting with neonatal-onset developmental and epileptic encephalopathy (Olson et al., 2018); in addition to recurrent phenotypes such as epilepsy and developmental delay/intellectual disability, three cases in this report presented with autism spectrum disorder/autistic disorder, and six cases presented with stereotypies.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2020
S
icon
S

Score remained at S

Description

A recurrent de novo missense variant in the PACS2 gene (p.Glu209Lys) was identified in 14 unrelated individuals presenting with neonatal-onset developmental and epileptic encephalopathy (Olson et al., 2018); in addition to recurrent phenotypes such as epilepsy and developmental delay/intellectual disability, three cases in this report presented with autism spectrum disorder/autistic disorder, and six cases presented with stereotypies.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

A recurrent de novo missense variant in the PACS2 gene (p.Glu209Lys) was identified in 14 unrelated individuals presenting with neonatal-onset developmental and epileptic encephalopathy (Olson et al., 2018); in addition to recurrent phenotypes such as epilepsy and developmental delay/intellectual disability, three cases in this report presented with autism spectrum disorder/autistic disorder, and six cases presented with stereotypies.

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Score remained at S

Description

A recurrent de novo missense variant in the PACS2 gene (p.Glu209Lys) was identified in 14 unrelated individuals presenting with neonatal-onset developmental and epileptic encephalopathy (Olson et al., 2018); in addition to recurrent phenotypes such as epilepsy and developmental delay/intellectual disability, three cases in this report presented with autism spectrum disorder/autistic disorder, and six cases presented with stereotypies.

Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019] [Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.2019]
Krishnan Probability Score

Score 0.49264271040963

Ranking 4457/25841 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 0.99932451549158

Ranking 991/18225 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
Iossifov Probability Score

Score 0.809

Ranking 227/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.85824249760714

Ranking 3776/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.22492893133714

Ranking 15916/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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