rs121908630
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP5
The NM_005476.7(GNE):c.673G>A(p.Asp225Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000435 in 1,610,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005476.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.766G>A | p.Asp256Asn | missense_variant | Exon 4 of 12 | 1 | NM_001128227.3 | ENSP00000379839.3 | ||
GNE | ENST00000642385.2 | c.673G>A | p.Asp225Asn | missense_variant | Exon 4 of 12 | NM_005476.7 | ENSP00000494141.2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1458648Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2AN XY: 725886
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74334
ClinVar
Submissions by phenotype
GNE myopathy Pathogenic:2Uncertain:1
Variant summary: GNE c.766G>A (p.Asp256Asn) results in a conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251392 control chromosomes. c.766G>A has been reported in the literature in four individuals affected with Inclusion Body Myopathy 2 from a single family, in the compound heterozygous state (Eisenberg_2001). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as VUS while one classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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Sialuria;C1853926:GNE myopathy Pathogenic:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 256 of the GNE protein (p.Asp256Asn). This variant is present in population databases (rs121908630, gnomAD 0.02%). This missense change has been observed in individual(s) with GNE-related myopathy (PMID: 11528398). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as D225N. ClinVar contains an entry for this variant (Variation ID: 6031). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. For these reasons, this variant has been classified as Pathogenic. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at