HOMER2

Chr 15

homer scaffold protein 2

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

NCBI Gene: 9455 ENSG00000103942 UniProt: Q9NSB8

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.

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtDeafness, autosomal dominant, 68

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · nonsyndromic genetic hearing loss · AD · ClinGen 2020

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.66

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in HOMER2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

493 rare PASS variants

Rare truncating (LoF)

1 in 2,100

75 rare PASS variants

Rare synonymous (reference)

1 in 230

172 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HOMER2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 1,900
South Asian	~43k	1 in 120	1 in 7,200
Remaining (unassigned)	~30k	1 in 120	1 in 2,700
European (Finnish)	~27k	1 in 530	≈ 1 in 8,700
Admixed American	~22k	1 in 110	≈ 1 in 4,500
African / African American	~21k	1 in 73	1 in 1,700
East Asian	~20k	1 in 120	1 in 820
Ashkenazi Jewish	~13k	1 in 730	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 130	≈ 1 in 2,600

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 9 coding exons well covered in gnomAD exomes; exons 1, 4 marginal. Genomes: all 9.? see exons ↓