HERC2

HECT and RLD domain containing E3 ubiquitin protein ligase 2, the group of HECT and RLD domain containing E3 ubiquitin protein ligases|Zinc fingers ZZ-type

Basic information

Region (hg38): 15:28111039-28322179

Links

ENSG00000128731 ∙ NCBI:8924 ∙ OMIM:605837 ∙ HGNC:4868 ∙ Uniprot:O95714 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental delay with autism spectrum disorder and gait instability (Supportive), mode of inheritance: AR
• developmental delay with autism spectrum disorder and gait instability (Moderate), mode of inheritance: AR
• developmental delay with autism spectrum disorder and gait instability (Strong), mode of inheritance: AR
• developmental delay with autism spectrum disorder and gait instability (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, autosomal recessive 38; Skin/hair/eye pigmentation 1	AD/AR	General	Skin/hair/eye pigmentation 1 may not have clinical relevance, but may act a susceptibility factor locus for a multifactorial disease (melanoma); For Nonsyndromic intellectual disability, autism, and gait disturbance, 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	Dermatologic; Neurologic	17952075; 18172690; 18252221; 18252222; 21471978; 21926416; 22065085; 22234890; 23065719; 23243086

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HERC2 gene.

• not provided (384 variants)
• Inborn genetic diseases (193 variants)
• Developmental delay with autism spectrum disorder and gait instability (77 variants)
• not specified (21 variants)
• Prader-Willi syndrome (6 variants)
• See cases (4 variants)
• Developmental delay with autism spectrum disorder and gait instability;Prader-Willi syndrome;SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (3 variants)
• SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (2 variants)
• Global developmental delay (1 variants)
• 10 conditions (1 variants)
• SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES;Prader-Willi syndrome;Developmental delay with autism spectrum disorder and gait instability (1 variants)
• Autosomal dominant nonsyndromic hearing loss 6;Wolfram-like syndrome;Wolfram syndrome 1 (1 variants)
• HERC2-related condition (1 variants)
• SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES;Developmental delay with autism spectrum disorder and gait instability (1 variants)
• 8 conditions (1 variants)
• Prader-Willi syndrome;SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES;Developmental delay with autism spectrum disorder and gait instability (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HERC2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	107	20	132
missense			382	17	8	407
nonsense	3	3	1			7
start loss						0
frameshift	2	3	1		1	7
inframe indel			3			3
splice donor/acceptor (+/-2bp)	1	1				2
splice region			12	13		25
non coding			4	3	6	13
Total	6	7	396	127	35

Highest pathogenic variant AF is 0.00151

Variants in HERC2

This is a list of pathogenic ClinVar variants found in the HERC2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-28111770-C-T		Developmental delay with autism spectrum disorder and gait instability • Inborn genetic diseases	Uncertain significance (Mar 07, 2024)
15-28111773-G-A		Inborn genetic diseases	Uncertain significance (Aug 17, 2021)
15-28111843-C-T		Inborn genetic diseases	Uncertain significance (Feb 21, 2024)
15-28111846-C-T			Uncertain significance (Nov 03, 2023)
15-28111873-T-C		Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 18, 2022)
15-28111932-T-C			Uncertain significance (Feb 06, 2022)
15-28113108-G-A			Uncertain significance (Nov 01, 2019)
15-28113136-C-T		Inborn genetic diseases	Uncertain significance (Jun 29, 2023)
15-28113167-G-A			Likely benign (Jun 04, 2018)
15-28113185-C-T			Benign/Likely benign (Mar 01, 2024)
15-28113197-C-G			Uncertain significance (Apr 15, 2022)
15-28113207-G-A		Inborn genetic diseases	Uncertain significance (May 23, 2023)
15-28113211-C-T		Inborn genetic diseases	Uncertain significance (Mar 28, 2023)
15-28113245-C-T			Likely benign (May 01, 2022)
15-28113287-C-T		Inborn genetic diseases	Likely benign (Jun 09, 2022)
15-28113577-G-A		Inborn genetic diseases	Uncertain significance (Jul 07, 2022)
15-28113626-C-T			Uncertain significance (Mar 14, 2019)
15-28113673-T-C			Likely benign (Apr 01, 2024)
15-28114598-G-A		Developmental delay with autism spectrum disorder and gait instability	Benign (Aug 10, 2021)
15-28114618-T-C		Inborn genetic diseases	Uncertain significance (Feb 08, 2023)
15-28114631-G-A			Uncertain significance (Jul 28, 2023)
15-28114642-G-A		Inborn genetic diseases	Uncertain significance (Jul 02, 2023)
15-28114646-G-A		Inborn genetic diseases	Uncertain significance (Oct 10, 2023)
15-28114664-G-A		Developmental delay with autism spectrum disorder and gait instability	Uncertain significance (Feb 26, 2019)
15-28114740-C-A		Inborn genetic diseases	Uncertain significance (Oct 14, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HERC2	protein_coding	protein_coding	ENST00000261609	92	211113

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	4.49e-13	125665	0	83	125748	0.000330

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.42	2105	2.76e+3	0.763	0.000174	31256
Missense in Polyphen		422	902.86	0.46741		9744
Synonymous	-2.51	1257	1.15e+3	1.09	0.0000820	9783
Loss of Function	12.1	36	236	0.152	0.0000123	2743

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00176	0.00174
Ashkenazi Jewish	0.000398	0.000397
East Asian	0.000395	0.000326
Finnish	0.000317	0.000185
European (Non-Finnish)	0.000204	0.000202
Middle Eastern	0.000395	0.000326
South Asian	0.000299	0.000294
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase that regulates ubiquitin- dependent retention of repair proteins on damaged chromosomes. Recruited to sites of DNA damage in response to ionizing radiation (IR) and facilitates the assembly of UBE2N and RNF8 promoting DNA damage-induced formation of 'Lys-63'-linked ubiquitin chains. Acts as a mediator of binding specificity between UBE2N and RNF8. Involved in the maintenance of RNF168 levels. E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of XPA which influences the circadian oscillation of DNA excision repair activity. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333). {ECO:0000269|PubMed:20023648, ECO:0000269|PubMed:20304803, ECO:0000269|PubMed:22508508, ECO:0000269|PubMed:26692333}.
• Disease: DISEASE: Mental retardation, autosomal recessive 38 (MRT38) [MIM:615516]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT38 is characterized by global developmental delay affecting motor, speech, adaptive, and social development. Patients manifest autistic features, aggression, self-injury, impulsivity, and distractibility. {ECO:0000269|PubMed:23065719}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ubiquitin mediated proteolysis - Homo sapiens (human);Prader-Willi and Angelman Syndrome;HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);DNA Repair;Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;SUMOylation of DNA damage response and repair proteins;Homology Directed Repair;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;G2/M DNA damage checkpoint;G2/M Checkpoints;Cell Cycle Checkpoints;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;SUMOylation;Cell Cycle;Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks;DNA Double Strand Break Response;Processing of DNA double-strand break ends (Consensus)

Recessive Scores

• pRec: 0.216

Intolerance Scores

• loftool: 0.307
• rvis_EVS: -5.99
• rvis_percentile_EVS: 0.05

Haploinsufficiency Scores

• pHI: 0.245
• hipred: Y
• hipred_score: 0.637
• ghis: 0.547

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.794

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Herc2
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype

Gene ontology

• Biological process: double-strand break repair via nonhomologous end joining;intracellular protein transport;cellular response to DNA damage stimulus;spermatogenesis;protein ubiquitination;proteasome-mediated ubiquitin-dependent protein catabolic process
• Cellular component: nucleus;nucleoplasm;cytoplasm;centriole;membrane
• Molecular function: ubiquitin-protein transferase activity;guanyl-nucleotide exchange factor activity;protein binding;zinc ion binding;ubiquitin protein ligase binding;SUMO binding