rs746079387
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_006736.6(DNAJB2):c.196G>A(p.Asp66Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D66Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_006736.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAJB2 | NM_006736.6 | c.196G>A | p.Asp66Asn | missense_variant | 4/9 | ENST00000336576.10 | |
DNAJB2 | NM_001039550.2 | c.196G>A | p.Asp66Asn | missense_variant | 4/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAJB2 | ENST00000336576.10 | c.196G>A | p.Asp66Asn | missense_variant | 4/9 | 1 | NM_006736.6 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251260Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135802
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461746Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22AN XY: 727156
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74332
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 26, 2019 | The p.D66N variant (also known as c.196G>A), located in coding exon 3 of the DNAJB2 gene, results from a G to A substitution at nucleotide position 196. The aspartic acid at codon 66 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Neuronopathy, distal hereditary motor, autosomal recessive 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 66 of the DNAJB2 protein (p.Asp66Asn). This variant is present in population databases (rs746079387, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNAJB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 578733). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at