HOMER2

protein-coding

homer scaffold protein 2, the group of Homer scaffold proteins

Gene summary

This gene encodes a member of the homer family of dendritic proteins. Members of this family regulate group 1 metabotrophic glutamate receptor function. The encoded protein is a postsynaptic density scaffolding protein. Alternative splicing results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 14. [provided by RefSeq, Jun 2011]

MANE transcript

NM_004839.4

Inheritance

ClinVar variants

P:3U:105B:60

Top phenotype

Deafness, autosomal dominant 68

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr15:82,836,946-82,986,153

External References & Databases

Ensembl (ENSG00000103942)

Transcript & Mutation Effects

hg38 • Region Span ~149.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

HOMER2 was described in association with autosomal dominant nonsyndromic hearing loss in 2015 by Azaiez et al. (25816005). At least 1 missense variant and 1 frameshift variant have been reported in humans (25816005, 30047143). Variants in this gene segregated with disease in 17 additional family members. Evidence supporting this gene-disease association includes case-level, segregation and experimental evidence. In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 8/31/2020.

autosomal dominant nonsyndromic hearing loss 68STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014740

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing loss 68MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014740

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing loss 68STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014740

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 68AD

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: 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: 25816005

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HOMER2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 169

Inborn genetic diseasesTotal: 56

not specifiedTotal: 42

HOMER2-related disorderTotal: 32

Autosomal dominant nonsyndromic hearing loss 68Total: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004839.4. 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			3 clinvar	32 clinvar		35
missense			95 clinvar	26 clinvar	1 clinvar	122
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift	2 clinvar	1 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)			4 clinvar	1 clinvar		5
Total	2	1	105	59	1	168

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004839.4	RefSeq	NP_004830.2	9	MANE Select
ENST00000450735.7	Ensembl	ENSP00000407634.2	9	MANE Select
NM_199330.3	RefSeq	NP_955362.1	9	Standard
ENST00000304231.12	Ensembl	ENSP00000305632.8	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
homer2	Danio rerio	Structure: olfactory bulb glomerulus Quality: aplastic/hypoplastic abnormal

Gene / Model

Organism

Observed Phenotype

homer2

Danio rerio

Structure: olfactory bulb glomerulus

Quality: aplastic/hypoplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glutamatergic synapse - Homo sapiens (human)
FoxO signaling pathway - Homo sapiens (human)
Neuronal System
Neurexins and neuroligins
Protein-protein interactions at synapses

Biological Process

G protein-coupled glutamate receptor signaling pathway
sensory perception of sound
regulation of G protein-coupled receptor signaling pathway
negative regulation of interleukin-2 production
calcium-mediated signaling using intracellular calcium source

Molecular Function

actin binding
protein binding
protein domain specific binding
GKAP/Homer scaffold activity
G protein-coupled glutamate receptor binding

Cellular Component

cytoplasm
cytosol
plasma membrane
postsynaptic density
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304231
Coding exons: 9
Length: 144824
Individuals with no LoFs: 124763
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 124784
p: 0.0000841

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.314	195	208	0.939	0.0000120	2343
Missense (PolyPhen)		55	64.765	0.84923		703
Synonymous	0.492	77	82.7	0.931	0.00000524	644
Loss of Function	2.69	7	20.0	0.351	0.00000102	232

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00019	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0	0.0	absent
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Postsynaptic density scaffolding protein. Binds and cross-links cytoplasmic regions of GRM1, GRM5, ITPR1, DNM3, RYR1, RYR2, SHANK1 and SHANK3. By physically linking GRM1 and GRM5 with ER-associated ITPR1 receptors, it aids the coupling of surface receptors to intracellular calcium release. May also couple GRM1 to PI3 kinase through its interaction with AGAP2. Isoforms can be differently regulated and may play an important role in maintaining the plasticity at glutamatergic synapses (PubMed:9808459). Required for normal hearing (PubMed:25816005). Negatively regulates T cell activation through negative regulation of IL2 expression by inhibiting calcineurin-NFAT pathway activation through interaction with NFATC2 (PubMed:18218901). {ECO:0000269|PubMed:18218901, ECO:0000269|PubMed:25816005, ECO:0000269|PubMed:9808459}.;
Disease: DISEASE: Deafness, autosomal dominant, 68 (DFNA68) [MIM:616707]: A form of non-syndromic sensorineural hearing loss with postlingual onset. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:25816005}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.213

Intolerance Scores

LoFtool: 0.530
RVIS EVS: 0.13
RVIS percentile EVS: 63.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.855

Gene Damage Prediction

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