DNAJB6

Chr 7AD

DnaJ heat shock protein family (Hsp40) member B6

Also known as: DJ4, DnaJ, HHDJ1, HSJ-2, HSJ2, LGMD1D, LGMD1E, LGMDD1

NCBI Gene: 10049 ENSG00000105993 UniProt: O75190 OMIM: 611332

The DNAJB6 protein functions as a molecular chaperone involved in protein folding and oligomeric protein complex assembly, and may regulate polyglutamine aggregation in neurons. Mutations cause autosomal dominant limb-girdle muscular dystrophy type 1 through an unknown pathogenic mechanism. The high pLI score (0.85) and low LOEUF score (0.40) indicate this gene is highly intolerant to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the DNAJ protein family. DNAJ family members are characterized by a highly conserved amino acid stretch called the 'J-domain' and function as one of the two major classes of molecular chaperones involved in a wide range of cellular events, such as protein folding and oligomeric protein complex assembly. This family member may also play a role in polyglutamine aggregation in specific neurons. Alternative splicing of this gene results in multiple transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Muscular dystrophy, limb-girdle, autosomal dominant 1MIM #603511

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · muscular dystrophy, limb-girdle, autosomal dominant · AD · ClinGen 2024

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

0.40

LOEUF

Mechanism· predicted

📖

GeneReview available — DNAJB6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.854

Z-score 3.46

OE 0.15 (0.07–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.17Z-score

OE missense 0.76 (0.67–0.87)

148 obs / 194.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.07–0.40)

0≤0.351.4

Missense OE?0.76 (0.67–0.87)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 3 / 19.5Missense obs/exp: 148 / 194.0Syn Z: -1.16

Background carrier burden — how many people carry a rare variant somewhere in DNAJB6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

440 rare PASS variants

Rare truncating (LoF)

1 in 2,500

58 rare PASS variants

Rare synonymous (reference)

1 in 300

195 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DNAJB6. 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 140	1 in 2,800
South Asian	~43k	1 in 110	1 in 5,300
Remaining (unassigned)	~30k	1 in 140	1 in 4,600
European (Finnish)	~27k	1 in 320	1 in 5,000
Admixed American	~22k	1 in 130	1 in 3,300
African / African American	~21k	1 in 160	1 in 2,300
East Asian	~20k	1 in 120	≈ 1 in 4,700
Ashkenazi Jewish	~13k	1 in 1,300	1 in 1,100
Middle Eastern	~2,884	1 in 220	≈ 1 in 2,400

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): 8 of 9 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 9.? see exons ↓