rs104894620
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2
The ENST00000494511.7(PMP22):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
PMP22
ENST00000494511.7 start_lost
ENST00000494511.7 start_lost
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 9.16
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in ENST00000494511.7 (PMP22) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 531685
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMP22 | NM_000304.4 | c.206T>G | p.Met69Arg | missense_variant | 4/5 | ENST00000312280.9 | NP_000295.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PMP22 | ENST00000312280.9 | c.206T>G | p.Met69Arg | missense_variant | 4/5 | 1 | NM_000304.4 | ENSP00000308937.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Pathogenic
D;D;D;D;D;.;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.;.;.;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;D;.;D;.;.;.;D
REVEL
Pathogenic
Sift
Uncertain
.;D;D;.;D;.;.;.;D
Sift4G
Uncertain
D;D;D;.;D;.;.;.;D
Polyphen
D;D;D;.;.;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);.;.;Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);
MVP
MPC
1.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at