HERC2

protein-coding

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

Gene summary

This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16. [provided by RefSeq, Mar 2012]

MANE transcript

NM_004667.6

Inheritance

AR, AD

ClinVar variants

P:31U:929B:348

Top phenotype

Intellectual developmental disorder, autosomal recessive 38; Skin/hair/eye pigmentation 1

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr15:28,111,040-28,322,179

External References & Databases

Ensembl (ENSG00000128731)

Transcript & Mutation Effects

hg38 • Region Span ~211.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay with autism spectrum disorder and gait instabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014224

Submitter: Orphanet

developmental delay with autism spectrum disorder and gait instabilitySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014224

Submitter: Labcorp Genetics (formerly Invitae)

developmental delay with autism spectrum disorder and gait instabilitySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014224

Submitter: PanelApp Australia

developmental delay with autism spectrum disorder and gait instabilityMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014224

Submitter: Ambry Genetics

developmental delay with autism spectrum disorder and gait instabilitySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014224

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 38; Skin/hair/eye pigmentation 1AD/AR

Manifestation: Dermatologic; Neurologic

Intervention: General

Rationale: 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

Refs: 17952075; 18172690; 18252221; 18252222; 21471978; 21926416; 22065085; 22234890; 23065719; 23243086

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HERC2 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 680

Inborn genetic diseasesTotal: 598

not specifiedTotal: 225

Developmental delay with autism spectrum disorder and gait instabilityTotal: 125

HERC2-related disorderTotal: 89

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYESTotal: 21

Prader-Willi syndromeTotal: 12

See casesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004667.6. 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			19 clinvar	275 clinvar	9 clinvar	303
missense	1 clinvar	3 clinvar	884 clinvar	56 clinvar	7 clinvar	951
nonsense	4 clinvar	6 clinvar	4 clinvar			14
start loss			1 clinvar			1
frameshift	3 clinvar	9 clinvar	1 clinvar		1 clinvar	14
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	20 clinvar			25
Total	9	22	929	331	17	1308

Highest pathogenic variant AF is 0.00042785768

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004667.6	RefSeq	NP_004658.3	92	MANE Select
ENST00000261609.13	Ensembl	ENSP00000261609.8	92	MANE Select
ENST00000564734.5	Ensembl	ENSP00000456237.1	3	Standard
ENST00000569772.1	Ensembl	ENSP00000457745.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

double-strand break repair via nonhomologous end joining
intracellular protein transport
cellular response to DNA damage stimulus
spermatogenesis
protein ubiquitination

Molecular Function

ubiquitin-protein transferase activity
guanyl-nucleotide exchange factor activity
protein binding
zinc ion binding
ubiquitin protein ligase binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
centriole
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261609
Coding exons: 92
Length: 211113
Individuals with no LoFs: 125665
Homozygous LoFs: 0
Heterozygous LoFs: 83
Defined: 125748
p: 0.000330

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.42	2105	2.76e+3	0.763	0.000174	31256
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0013	0.0012	notable
Latino/Admixed American	0.00051	0.00049	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00040	0.00033	rare
Finnish	0.00032	0.00018	rare
European (Non-Finnish)	0.00020	0.00020	rare
South Asian	0.00030	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.216

Intolerance Scores

LoFtool: 0.307
RVIS EVS: -5.99
RVIS percentile EVS: 0.05

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.794

Gene Damage Prediction

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