rs864622678
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000304.4(PMP22):c.280_281delinsT(p.Gly94SerfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
PMP22
NM_000304.4 frameshift
NM_000304.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.74
Genes affected
PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 53 pathogenic variants in the truncated region.
PP5
?
Variant 17-15239509-CC-A is Pathogenic according to our data. Variant chr17-15239509-CC-A is described in ClinVar as [Pathogenic]. Clinvar id is 220861.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMP22 | NM_000304.4 | c.280_281delinsT | p.Gly94SerfsTer17 | frameshift_variant | 4/5 | ENST00000312280.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMP22 | ENST00000312280.9 | c.280_281delinsT | p.Gly94SerfsTer17 | frameshift_variant | 4/5 | 1 | NM_000304.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease, type I Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2015 | This sequence change deletes 2 nucleotides and inserts 1 nucleotide in exon 4 of the PMP22 mRNA (c.280_281delinsT), causing a frameshift at codon 94. This creates a premature translational stop signal in the last exon of the PMP22 mRNA (p.Gly94Serfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated PMP22 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. This variant has been observed to occur de novo in an affected individual tested at Invitae. In addition, a different variant (NM_000304.3:c.281delG) giving rise to a very similar protein effect  (p.Gly94Alafs*17) has been reported in several patients affected with CMT and Dejerine−Sottas syndrome (PMID: 9324088, 11545686, 11835375, 19067730, 26392352), which also suggests that the sequence change observed here is disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at