chr8-81443409-C-T
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_002677.5(PMP2):c.388G>A(p.Glu130Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00004 in 1,599,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
PMP2
NM_002677.5 missense
NM_002677.5 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 1.71
Genes affected
PMP2 (HGNC:9117): (peripheral myelin protein 2) The protein encoded by this gene localizes to myelin sheaths of the peripheral nervous system. The encoded protein can bind both the membrane layers of the sheaths and monomeric lipids, and is thought to provide stability to the sheath. A defect in this gene was shown to be a cause of dominant demyelinating CMT neuropathy. [provided by RefSeq, Jan 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.32496127).
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMP2 | NM_002677.5 | c.388G>A | p.Glu130Lys | missense_variant | 4/4 | ENST00000256103.3 | |
PMP2 | NM_001348381.2 | c.*32G>A | 3_prime_UTR_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMP2 | ENST00000256103.3 | c.388G>A | p.Glu130Lys | missense_variant | 4/4 | 1 | NM_002677.5 | P1 | |
PMP2 | ENST00000519260.1 | c.*32G>A | 3_prime_UTR_variant | 3/3 | 1 | ||||
ENST00000524085.2 | n.298+3316C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152120Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000249 AC: 6AN: 240498Hom.: 0 AF XY: 0.0000230 AC XY: 3AN XY: 130308
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GnomAD4 exome AF: 0.0000401 AC: 58AN: 1447658Hom.: 0 Cov.: 27 AF XY: 0.0000389 AC XY: 28AN XY: 720270
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152120Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74308
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2023 | The c.388G>A (p.E130K) alteration is located in exon 4 (coding exon 4) of the PMP2 gene. This alteration results from a G to A substitution at nucleotide position 388, causing the glutamic acid (E) at amino acid position 130 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 13, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 130 of the PMP2 protein (p.Glu130Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PMP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1468497). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of methylation at E130 (P = 0.0102);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at