Human Gene Module / Chromosome 15 / HERC2

HERC2HECT and RLD domain containing E3 ubiquitin protein ligase 2

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
17 / 0
Aliases
HERC2, D15F37S1,  SHEP1,  jdf2,  p528
Associated Syndromes
-
Chromosome Band
15q13.1
Associated Disorders
DD/NDD, ASD, EPS
Relevance to Autism

Genome-wide mapping and exome sequencing of seven affected children in three separate sibships from the Mennonite (Plain) community identified a homozygous missense variant in the HERC2 gene (c.1781C>T; p.Pro594Leu) in all seven affected children, who presented with global developmental delay/mental retardation, autistic behavior, and gait instability (Puffenberger et al., 2012). No homozygotes or heterozygotes for this variant were found in 380 control samples from the Lancaster Amish and Lancaster Mennonite community.

Molecular Function

E3 ubiquitin-protein ligase that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes. Genetic variants in HERC2 define the skin/hair/eye pigmentation variation locus 1 (SHEP1) [MIM:227220].

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HERC2 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder Puffenberger EG , et al. (2012) No ASD
2 Support Mutation of HERC2 causes developmental delay with Angelman-like features Harlalka GV , et al. (2012) No -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
5 Support Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype Morice-Picard F , et al. (2016) No -
6 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No DD, epilepsy/seizures, hypotonia
7 Support Proteomic investigations of human HERC2 mutants: Insights into the pathobiology of a neurodevelopmental disorder Abraham JR , et al. (2019) No -
8 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.5464+5G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.3050+7C>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.11636T>C p.Met3879Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.9486C>T p.Asp3162%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.12234G>A p.Pro4078%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.6064C>T p.Arg2022Trp missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Both parents Simplex 27759030 Morice-Picard F , et al. (2016)
c.13026C>A p.Pro4342%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2236C>T p.Arg746Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4676-1G>A - splice_site_variant Familial Both parents - 27848944 Trujillano D , et al. (2016)
c.9364_9370del p.Thr3122AlafsTer17 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.9170G>A p.Arg3057Gln missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.3203G>A p.Gly1068Glu missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.6514C>T p.Arg2172Cys missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.1781C>T p.Pro594Leu missense_variant Familial Both parents Multiplex 23243086 Harlalka GV , et al. (2012)
c.1781C>T p.Pro594Leu missense_variant Familial Both parents Multiplex 23065719 Puffenberger EG , et al. (2012)
c.1781C>T p.Pro594Leu missense_variant Familial Both parents Multi-generational 23243086 Harlalka GV , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A homozygous missense variant in the HERC2 gene (c.1781C>T; p.Pro594Leu) has been observed in multiple Old Order Amish pedigrees exhibiting an autosomal recessive neuordevelopmental disorder with some phenotypic similarities to Angelman syndrome characterized by global developmental delay/intellectual disability, behavioral abnormalities including autistic behavior, hypotonia, gait instability, and subtle dysmorphic features, including bright blue irides (Puffenberger et al., 2012; Harlalka et al., 2013). A de novo possibly damaging missense variant in HERC2 was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014).

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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

A homozygous missense variant in the HERC2 gene (c.1781C>T; p.Pro594Leu) has been observed in multiple Old Order Amish pedigrees exhibiting an autosomal recessive neuordevelopmental disorder with some phenotypic similarities to Angelman syndrome characterized by global developmental delay/intellectual disability, behavioral abnormalities including autistic behavior, hypotonia, gait instability, and subtle dysmorphic features, including bright blue irides (Puffenberger et al., 2012; Harlalka et al., 2013). A de novo possibly damaging missense variant in HERC2 was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014).

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

Score remained at S

Description

A homozygous missense variant in the HERC2 gene (c.1781C>T; p.Pro594Leu) has been observed in multiple Old Order Amish pedigrees exhibiting an autosomal recessive neuordevelopmental disorder with some phenotypic similarities to Angelman syndrome characterized by global developmental delay/intellectual disability, behavioral abnormalities including autistic behavior, hypotonia, gait instability, and subtle dysmorphic features, including bright blue irides (Puffenberger et al., 2012; Harlalka et al., 2013). A de novo possibly damaging missense variant in HERC2 was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014).

Reports Added
[Proteomic investigations of human HERC2 mutants: Insights into the pathobiology of a neurodevelopmental disorder.2019] [Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
10/1/2016
S
icon
S

Score remained at S

Description

A homozygous missense variant in the HERC2 gene (c.1781C>T; p.Pro594Leu) has been observed in multiple Old Order Amish pedigrees exhibiting an autosomal recessive neuordevelopmental disorder with some phenotypic similarities to Angelman syndrome characterized by global developmental delay/intellectual disability, behavioral abnormalities including autistic behavior, hypotonia, gait instability, and subtle dysmorphic features, including bright blue irides (Puffenberger et al., 2012; Harlalka et al., 2013). A de novo possibly damaging missense variant in HERC2 was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014).

Reports Added
[Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
Krishnan Probability Score

Score 0.50034820084737

Ranking 2083/25841 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 1

Ranking 13/18225 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 0.898

Ranking 142/239 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 0.95067469863532

Ranking 18585/18665 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
Larsen Cumulative Evidence Score

Score 12

Ranking 160/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.514949489543

Ranking 410/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CCDC65 Coiled-coil domain-containing protein 65 Human Protein Binding 85478 Q8IXS2-2
DNAJB5 DnaJ homolog subfamily B member 5 Human Protein Binding 25822 O75953
gag-pol Gag-Pol polyprotein HIV-1 Protein Binding 155348 P04585
RNF115 E3 ubiquitin-protein ligase RNF115 Human Protein Binding 27246 Q9Y4L5
RNF166 RING finger protein 166 Human Protein Binding 115992 Q96A37
SPZ1 Spermatogenic leucine zipper protein 1 Human Protein Binding 84654 Q9BXG8
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