NM_002677.5:c.365G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002677.5(PMP2):c.365G>A(p.Gly122Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,600,130 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G122G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 63 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 63 hom. )

Consequence

PMP2
NM_002677.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.737

Variant links:

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]

PMP2 links:

ENSG00000253859 (HGNC:):

ENSG00000253859 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018780828).

BP6

Variant 8-81443432-C-T is Benign according to our data. Variant chr8-81443432-C-T is described in ClinVar as [Benign]. Clinvar id is 768248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-81443432-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP2	NM_002677.5 link	c.365G>A	p.Gly122Asp	missense_variant	Exon 4 of 4	ENST00000256103.3	NP_002668.1
PMP2	NM_001348381.2 link	c.*9G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001335310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PMP2	ENST00000256103.3 link	c.365G>A	p.Gly122Asp	missense_variant	Exon 4 of 4	1	NM_002677.5	ENSP00000256103.2	P02689
PMP2	ENST00000519260 link	c.*9G>A		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000429917.1	E5RH45
ENSG00000253859	ENST00000524085.2 link	n.298+3339C>T		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2444

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0562

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00505

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.00411

AC:

992

AN:

241208

Hom.:

AF XY:

0.00279

AC XY:

365

AN XY:

130824

show subpopulations

Gnomad AFR exome

AF:

0.0542

Gnomad AMR exome

AF:

0.00343

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000692

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000824

Gnomad OTH exome

AF:

0.00223

GnomAD4 exome

AF:

0.00156

AC:

2259

AN:

1447922

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

987

AN XY:

720414

show subpopulations

Gnomad4 AFR exome

AF:

0.0559

Gnomad4 AMR exome

AF:

0.00372

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000838

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.0000552

Gnomad4 OTH exome

AF:

0.00314

GnomAD4 genome

AF:

0.0161

AC:

2443

AN:

152208

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1141

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0560

Gnomad4 AMR

AF:

0.00504

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.0132

Alfa

AF:

0.00167

Hom.:

Bravo

AF:

0.0185

ESP6500AA

AF:

0.0611

AC:

269

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00494

AC:

600

Asia WGS

AF:

0.00203

AC:

AN:

3468

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PMP2-related disorder

Benign:1

Jun 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.038

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.085

PrimateAI

Benign

0.37

PROVEAN

Benign

1.5

REVEL

Benign

0.088

Sift

Benign

0.98

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.14

MVP

0.32

MPC

0.13

ClinPred

0.0085

GERP RS

3.5

Varity_R

0.24

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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