NM_000304.4:c.255C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP3BS1_SupportingBS2

The NM_000304.4(PMP22):​c.255C>G​(p.Cys85Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

PMP22
NM_000304.4 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.33

Publications

0 publications found
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]
PMP22 Gene-Disease associations (from GenCC):
  • Charcot-Marie-Tooth disease type 1A
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
  • hereditary neuropathy with liability to pressure palsies
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
  • Charcot-Marie-Tooth disease type 1E
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
  • Charcot-Marie-Tooth disease type 3
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000304.4
PP3
MetaRNN computational evidence supports a deleterious effect, 0.799
BS1
Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000623 (91/1461682) while in subpopulation AFR AF = 0.000179 (6/33470). AF 95% confidence interval is 0.0000771. There are 0 homozygotes in GnomAdExome4. There are 42 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 91 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMP22NM_000304.4 linkc.255C>G p.Cys85Trp missense_variant Exon 4 of 5 ENST00000312280.9 NP_000295.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMP22ENST00000312280.9 linkc.255C>G p.Cys85Trp missense_variant Exon 4 of 5 1 NM_000304.4 ENSP00000308937.3 Q01453

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000159
AC:
4
AN:
251460
AF XY:
0.0000294
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000623
AC:
91
AN:
1461682
Hom.:
0
Cov.:
33
AF XY:
0.0000578
AC XY:
42
AN XY:
727168
show subpopulations
African (AFR)
AF:
0.000179
AC:
6
AN:
33470
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000747
AC:
83
AN:
1111846
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
6
12
17
23
29
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152248
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74382
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41466
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68046
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000302
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jun 28, 2021
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 03, 2019
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Distal spinal muscular atrophy Uncertain:1
Aug 14, 2019
Genesis Genome Database
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:research

- -

Inborn genetic diseases Uncertain:1
Nov 09, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.C85W variant (also known as c.255C>G), located in coding exon 3 of the PMP22 gene, results from a C to G substitution at nucleotide position 255. The cysteine at codon 85 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dejerine-Sottas disease;C0205713:Roussy-Lévy syndrome;C0270911:Charcot-Marie-Tooth disease, type IA;C0393814:Hereditary liability to pressure palsies;C3495591:Charcot-Marie-Tooth disease type 1E;C4083008:Guillain-Barre syndrome, familial Uncertain:1
Mar 16, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease, type I Uncertain:1
Dec 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 85 of the PMP22 protein (p.Cys85Trp). This variant is present in population databases (rs755701957, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with PMP22-related conditions. ClinVar contains an entry for this variant (Variation ID: 531692). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Uncertain
0.072
D
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.81
D;D;D;D;D;.;.;D;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.82
T;.;.;.;.;T;T;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.80
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.53
D
MutationAssessor
Uncertain
2.4
M;M;M;.;.;.;.;.;.
PhyloP100
3.3
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-2.8
.;D;D;.;D;.;.;.;D
REVEL
Uncertain
0.59
Sift
Benign
0.18
.;T;T;.;T;.;.;.;T
Sift4G
Benign
0.18
T;T;T;.;D;.;.;.;D
Polyphen
0.94
P;P;P;.;.;.;.;.;.
Vest4
0.70
MutPred
0.63
Gain of MoRF binding (P = 0.0688);Gain of MoRF binding (P = 0.0688);Gain of MoRF binding (P = 0.0688);Gain of MoRF binding (P = 0.0688);Gain of MoRF binding (P = 0.0688);.;.;Gain of MoRF binding (P = 0.0688);Gain of MoRF binding (P = 0.0688);
MVP
0.32
MPC
1.5
ClinPred
0.85
D
GERP RS
5.6
Varity_R
0.36
gMVP
0.84
Mutation Taster
=31/69
disease causing

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

Other links and lift over

dbSNP: rs755701957; hg19: chr17-15142852; API