Variant chr17-15239562-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_000304.4(PMP22):c.228C>G(p.Ser76Arg) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S76I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PMP22
NM_000304.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.629

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS1

Transcript NM_000304.4 (PMP22) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000304.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-15239563-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

PP5

Variant 17-15239562-G-C is Pathogenic according to our data. Variant chr17-15239562-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448088.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 linkuse as main transcript	c.228C>G	p.Ser76Arg	missense_variant	4/5	ENST00000312280.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMP22	ENST00000312280.9 linkuse as main transcript	c.228C>G	p.Ser76Arg	missense_variant	4/5	1	NM_000304.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Pathogenic

0.95

D;D;D;D;D;.;.;D;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.0029

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;.;.;.;.;D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

3.0

M;M;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;N

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.5

.;D;D;.;D;.;.;.;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0060

.;D;D;.;D;.;.;.;D

Sift4G

Benign

0.068

T;T;T;.;T;.;.;.;T

Polyphen

1.0

D;D;D;.;.;.;.;.;.

Vest4

0.77

MutPred

0.81

Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);.;.;Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);

MVP

0.76

MPC

1.2

ClinPred

0.98

GERP RS

-3.8

Varity_R

0.70

gMVP

0.98

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over