rs80338763

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000304.4(PMP22):​c.281del​(p.Gly94AlafsTer17) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

PMP22
NM_000304.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4U:2

Conservation

PhyloP100: 6.01
Variant links:
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 18 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.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-15239508-GC-G is Pathogenic according to our data. Variant chr17-15239508-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 30158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-15239508-GC-G is described in Lovd as [Pathogenic]. Variant chr17-15239508-GC-G is described in Lovd as [Pathogenic]. Variant chr17-15239508-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PMP22NM_000304.4 linkuse as main transcriptc.281del p.Gly94AlafsTer17 frameshift_variant 4/5 ENST00000312280.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PMP22ENST00000312280.9 linkuse as main transcriptc.281del p.Gly94AlafsTer17 frameshift_variant 4/51 NM_000304.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease Uncertain:2
Uncertain significance, no assertion criteria providedliterature onlyInherited Neuropathy Consortium-- -
Uncertain significance, no assertion criteria providedresearchGenesis Genome DatabaseAug 14, 2019- -
Charcot-Marie-Tooth disease, type IA Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2009- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJul 30, 2020PVS1_Strong, PS4_Moderate, PM2, PM6, PP4 -
Charcot-Marie-Tooth disease type 1E Pathogenic:1
Pathogenic, no assertion criteria providedresearchDepartment of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of KoreaFeb 11, 2019- -
Charcot-Marie-Tooth disease, type I Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeMar 18, 2022For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 30158). This premature translational stop signal has been observed in individual(s) with CMT and Dejerine‚àíSottas syndrome (PMID: 9324088, 11545686, 11835375, 19067730, 26392352). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly94Alafs*17) in the PMP22 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 67 amino acid(s) of the PMP22 protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338763; hg19: chr17-15142825; API