COMMD6

Chr 13

COMM domain containing 6

Also known as: Acrg

NCBI Gene: 170622 ENSG00000188243 UniProt: Q7Z4G1

COMMD6 encodes a scaffold protein essential for the commander complex that regulates endosomal recycling of transmembrane cargos and inhibits NF-kappa-B activation. Mutations cause autosomal recessive neurodevelopmental disorder with hypotonia, seizures, and brain abnormalities, with onset in infancy or early childhood. The gene shows moderate tolerance to loss-of-function variants, consistent with recessive inheritance patterns.

ResearchSummary from RefSeq, UniProt

COMMD6 belongs to a family of NF-kappa-B (see RELA; MIM 164014)-inhibiting proteins characterized by the presence of a COMM domain (see COMMD1; MIM 607238) (de Bie et al., 2006 [PubMed 16573520]).[supplied by OMIM, Mar 2009]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.99

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?

0.99LOEUF

pLI 0.172

Z-score 1.60

OE 0.31 (0.13–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.69Z-score

OE missense 1.27 (1.04–1.56)

65 obs / 51.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.31 (0.13–0.99)

0≤0.351.4

Missense OE?1.27 (1.04–1.56)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 2 / 6.3Missense obs/exp: 65 / 51.2Syn Z: -0.74

Background carrier burden — how many people carry a rare variant somewhere in COMMD6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 310

228 rare PASS variants

Rare truncating (LoF)

1 in 1,600

44 rare PASS variants

Rare synonymous (reference)

1 in 1,300

63 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for COMMD6. 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 470	1 in 1,500
South Asian	~43k	1 in 410	1 in 1,900
Remaining (unassigned)	~30k	1 in 270	1 in 1,100
European (Finnish)	~27k	1 in 1,600	≈ 1 in 27,000
Admixed American	~22k	1 in 190	1 in 1,700
African / African American	~21k	1 in 450	≈ 1 in 6,400
East Asian	~20k	1 in 910	1 in 1,000
Ashkenazi Jewish	~13k	≈ 1 in 13,000	none seen
Middle Eastern	~2,883	1 in 140	≈ 1 in 2,700

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): 3 of 4 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 4.? see exons ↓