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…

DNmechanismADLOEUF 0.401 OMIM phenotype

Clinical Summary— DNAJB6

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Gene-Disease Validity (ClinGen)

muscular dystrophy, limb-girdle, autosomal dominant · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 245 VUS of 525 total submissions

Explore recent and relevant literature in Research Assistant →

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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

This gene — mechanism propensity

0.7035th %ile

GOF

0.4480th %ile

LOF

0.51top 25%

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

DNFurthermore, immunofluorescence analyses and filter trap assay demonstrated that the c.287C>T (p.Pro96Leu) mutation possessed a dominant negative effect on the anti-aggregation function of DNAJB6 protein.1

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

References

1.PMID 28233300 ↗

ClinVar Variant Classifications

525 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic3

VUS245

Likely Benign164

Benign52

Conflicting38

Pathogenic

Likely Pathogenic

245

VUS

164

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	11	1	0	12
Likely Pathogenic	0	3	0	0	3
VUS	19	180	44	2	245
Likely Benign	0	7	89	68	164
Benign	0	0	50	2	52
Conflicting	—				38
Total	19	201	184	72	514

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

View in ClinVar →

88 pathogenic / likely-pathogenic (of 98) ClinVar copy-number / structural variants overlap DNAJB6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →