Genetic Variant NM_002677.5:c.353G>A (chr8-81443444-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002677.5(PMP2):c.353G>A(p.Cys118Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,596,186 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 (★). Synonymous variant affecting the same amino acid position (i.e. C118C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PMP2
NM_002677.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease, demyelinating, type 1G
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

PMP2 links:

ENSG00000253374 (HGNC:):

ENSG00000253374 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.078413814).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002677.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP2	NM_002677.5	MANE Select	c.353G>A	p.Cys118Tyr	missense	Exon 4 of 4	NP_002668.1	P02689
	PMP2	NM_001348381.2		c.180G>A	p.Met60Ile	missense	Exon 3 of 3	NP_001335310.1	E5RH45

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMP2	ENST00000256103.3	TSL:1 MANE Select	c.353G>A	p.Cys118Tyr	missense	Exon 4 of 4	ENSP00000256103.2	P02689
PMP2	ENST00000519260.1	TSL:1	c.180G>A	p.Met60Ile	missense	Exon 3 of 3	ENSP00000429917.1	E5RH45
PMP2	ENST00000910617.1		c.347G>A	p.Cys116Tyr	missense	Exon 4 of 4	ENSP00000580676.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152132

Hom.:

Cov.:

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:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

240124

AF XY:

0.0000154

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443936

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32816

American (AMR)

AF:

0.00

AC:

AN:

42918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25888

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39238

South Asian (SAS)

AF:

0.00

AC:

AN:

83038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101950

Other (OTH)

AF:

0.00

AC:

AN:

59762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.62

M_CAP

Benign

0.036

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.8

PhyloP100

2.1

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.14

Sift

Benign

0.083

Sift4G

Benign

0.11

Polyphen

0.047

Vest4

0.28

MVP

0.57

MPC

0.20

ClinPred

0.65

GERP RS

5.3

Varity_R

0.85

gMVP

0.93

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over