HOMER2

Chr 15AD

homer scaffold protein 2

Also known as: ACPD, CPD, DFNA68, HOMER-2, VESL-2

NCBI Gene: 9455 ENSG00000103942 UniProt: Q9NSB8 OMIM: 604799

The protein functions as a postsynaptic density scaffolding protein that binds and cross-links metabotrophic glutamate receptors with intracellular calcium release channels, coupling surface receptors to calcium signaling and maintaining plasticity at glutamatergic synapses. Mutations cause autosomal recessive neurodevelopmental disorder with seizures and hearing loss, affecting both neurological development and auditory function. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.66), consistent with its role in essential synaptic signaling pathways.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.661 OMIM phenotype

Clinical Summary— HOMER2

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 93 VUS of 225 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.009

Z-score 2.69

OE 0.35 (0.20–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.31Z-score

OE missense 0.94 (0.83–1.06)

195 obs / 207.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.20–0.66)

0≤0.351.4

Missense OE?0.94 (0.83–1.06)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 7 / 20.0Missense obs/exp: 195 / 207.7Syn Z: 0.49

This gene — mechanism propensity

0.79top 25%

GOF

0.5464th %ile

LOF

0.3549th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThese data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 25816005 ↗

ClinVar Variant Classifications

225 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS93

Likely Benign74

Benign32

Conflicting11

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	0	0	3
Likely Pathogenic	2	0	0	0	2
VUS	6	82	3	2	93
Likely Benign	1	14	34	25	74
Benign	0	2	26	4	32
Conflicting	—				11
Total	11	99	63	31	215

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

34 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap HOMER2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →