Variant 17-15259185-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000304.4(PMP22):c.87C>G(p.Ile29Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I29I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PMP22
NM_000304.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.143

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000304.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16193375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMP22	NM_000304.4 linkuse as main transcript	c.87C>G	p.Ile29Met	missense_variant	3/5	ENST00000312280.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMP22	ENST00000312280.9 linkuse as main transcript	c.87C>G	p.Ile29Met	missense_variant	3/5	1	NM_000304.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251406

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Uncertain

0.46

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

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.56

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

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.16

T;T;T;T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

-0.20

N;N;N;.;.;.;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

1.2

.;N;N;.;N;.;N

REVEL

Benign

0.17

Sift

Benign

0.11

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

Sift4G

Benign

0.21

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

Polyphen

0.036

B;B;B;.;.;.;.

Vest4

0.094

MutPred

0.53

Loss of catalytic residue at I29 (P = 0.335);Loss of catalytic residue at I29 (P = 0.335);Loss of catalytic residue at I29 (P = 0.335);Loss of catalytic residue at I29 (P = 0.335);Loss of catalytic residue at I29 (P = 0.335);Loss of catalytic residue at I29 (P = 0.335);Loss of catalytic residue at I29 (P = 0.335);

MVP

0.46

MPC

0.48

ClinPred

0.031

GERP RS

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over