chr2-219281937-A-G
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_006736.6(DNAJB2):c.230-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000613 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
DNAJB2
NM_006736.6 splice_acceptor, intron
NM_006736.6 splice_acceptor, intron
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.29
Genes affected
DNAJB2 (HGNC:5228): (DnaJ heat shock protein family (Hsp40) member B2) This gene is almost exclusively expressed in the brain, mainly in the neuronal layers. It encodes a protein that shows sequence similarity to bacterial DnaJ protein and the yeast homologs. In bacteria, this protein is implicated in protein folding and protein complex dissociation. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.12615384 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-219281937-A-G is Pathogenic according to our data. Variant chr2-219281937-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234675.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=4, not_provided=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DNAJB2 | NM_006736.6 | c.230-2A>G | splice_acceptor_variant, intron_variant | Intron 4 of 8 | ENST00000336576.10 | NP_006727.2 | ||
| DNAJB2 | NM_001039550.2 | c.230-2A>G | splice_acceptor_variant, intron_variant | Intron 4 of 9 | NP_001034639.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000125 AC: 19AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251262Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135822
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GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461746Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40AN XY: 727174
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GnomAD4 genome 0.000125 AC: 19AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74468
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2025 | Identified in an individual from a cohort with suspected Charcot-Marie-Tooth disease, however, it is unclear if this individual harbored a second DNAJB2 variant and clinical information was not provided (PMID: 32376792); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25274842, 22522442, 32376792) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 17, 2020 | PVS1, PM2 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Neuronopathy, distal hereditary motor, autosomal recessive 5 Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 17, 2024 | This sequence change affects an acceptor splice site in intron 4 of the DNAJB2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNAJB2 are known to be pathogenic (PMID: 22522442, 25274842). This variant is present in population databases (rs369661561, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 234675). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 18, 2024 | Variant summary: DNAJB2 c.230-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of DNAJB2 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251262 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DNAJB2 causing Young adult-onset distal hereditary motor neuropathy (6e-05 vs 0.0011), allowing no conclusion about variant significance. c.230-2A>G has been reported in the literature in at least one individual affected with clinical features of Charcot-Marie-Tooth disease without reported second variant (e.g. Volodarsky_2021). This report does not provide unequivocal conclusions about association of the variant with Young adult-onset distal hereditary motor neuropathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 234675). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 10, 2020 | The c.230-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the DNAJB2 gene. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The exact functional effect of the missing amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 2;C4749918:Neuronopathy, distal hereditary motor, autosomal recessive 5 Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely pathogenic and reported on 11-23-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 23
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at