rs372973038
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_058246.4(DNAJB6):c.230G>A(p.Gly77Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G77V) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
DNAJB6
NM_058246.4 missense
NM_058246.4 missense
Scores
12
6
Clinical Significance
Conservation
PhyloP100: 5.06
Genes affected
DNAJB6 (HGNC:14888): (DnaJ heat shock protein family (Hsp40) member B6) 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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
?
In a region_of_interest Interaction with HSP70 (size 144) in uniprot entity DNJB6_HUMAN there are 32 pathogenic changes around while only 4 benign (89%) in NM_058246.4
BS2
?
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAJB6 | NM_058246.4 | c.230G>A | p.Gly77Glu | missense_variant | 4/10 | ENST00000262177.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAJB6 | ENST00000262177.9 | c.230G>A | p.Gly77Glu | missense_variant | 4/10 | 1 | NM_058246.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152218Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251306Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135804
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GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461642Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 727114
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 77 of the DNAJB6 protein (p.Gly77Glu). This variant is present in population databases (rs372973038, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal dominant limb-girdle muscular dystrophy (PMID: 29970176). ClinVar contains an entry for this variant (Variation ID: 910286). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAJB6 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;D;.;T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;.
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;T;D;.
Sift4G
Uncertain
D;T;D;T;D;T;D;D
Polyphen
0.90, 0.88, 0.98
.;P;P;.;D;.;.;.
Vest4
0.64, 0.64, 0.62, 0.64
MVP
MPC
0.80
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at