Genetic Variant PMP2:c.349-30G>C (chr8-81443478-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002677.5(PMP2):c.349-30G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,452,084 control chromosomes in the GnomAD database, including 3,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 264 hom., cov: 32)

Exomes 𝑓: 0.064 ( 3035 hom. )

Consequence

PMP2
NM_002677.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.196

Publications

4 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 8-81443478-C-G is Benign according to our data. Variant chr8-81443478-C-G is described in ClinVar as Benign. ClinVar VariationId is 1267863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0893 is higher than 0.05.

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.349-30G>C		intron	N/A	NP_002668.1	P02689
	PMP2	NM_001348381.2		c.176-30G>C		intron	N/A	NP_001335310.1	E5RH45

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMP2	ENST00000256103.3	TSL:1 MANE Select	c.349-30G>C	intron	N/A	ENSP00000256103.2	P02689
PMP2	ENST00000519260.1	TSL:1	c.176-30G>C	intron	N/A	ENSP00000429917.1	E5RH45
PMP2	ENST00000910617.1		c.343-30G>C	intron	N/A	ENSP00000580676.1

Frequencies

GnomAD3 genomes

AF:

0.0564

AC:

8576

AN:

152018

Hom.:

264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0389

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0932

Gnomad ASJ

AF:

0.0617

Gnomad EAS

AF:

0.0694

Gnomad SAS

AF:

0.0655

Gnomad FIN

AF:

0.0246

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0613

Gnomad OTH

AF:

0.0704

GnomAD2 exomes

AF:

0.0662

AC:

14433

AN:

218182

AF XY:

0.0657

show subpopulations

Gnomad AFR exome

AF:

0.0402

Gnomad AMR exome

AF:

0.113

Gnomad ASJ exome

AF:

0.0627

Gnomad EAS exome

AF:

0.0730

Gnomad FIN exome

AF:

0.0247

Gnomad NFE exome

AF:

0.0644

Gnomad OTH exome

AF:

0.0764

GnomAD4 exome

AF:

0.0640

AC:

83184

AN:

1299948

Hom.:

3035

Cov.:

AF XY:

0.0636

AC XY:

41500

AN XY:

652382

show subpopulations

African (AFR)

AF:

0.0428

AC:

1236

AN:

28890

American (AMR)

AF:

0.112

AC:

4151

AN:

37206

Ashkenazi Jewish (ASJ)

AF:

0.0599

AC:

1458

AN:

24328

East Asian (EAS)

AF:

0.0643

AC:

2433

AN:

37818

South Asian (SAS)

AF:

0.0676

AC:

4984

AN:

73754

European-Finnish (FIN)

AF:

0.0258

AC:

1325

AN:

51290

Middle Eastern (MID)

AF:

0.107

AC:

583

AN:

5458

European-Non Finnish (NFE)

AF:

0.0645

AC:

63626

AN:

986630

Other (OTH)

AF:

0.0621

AC:

3388

AN:

54574

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

3505

7009

10514

14018

17523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2346

4692

7038

9384

11730

<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:

0.0565

AC:

8590

AN:

152136

Hom.:

264

Cov.:

AF XY:

0.0550

AC XY:

4087

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0391

AC:

1624

AN:

41532

American (AMR)

AF:

0.0933

AC:

1425

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0617

AC:

214

AN:

3470

East Asian (EAS)

AF:

0.0694

AC:

360

AN:

5186

South Asian (SAS)

AF:

0.0658

AC:

317

AN:

4820

European-Finnish (FIN)

AF:

0.0246

AC:

260

AN:

10582

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0612

AC:

4161

AN:

67956

Other (OTH)

AF:

0.0735

AC:

155

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

424

847

1271

1694

2118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0578

Hom.:

Bravo

AF:

0.0628

Asia WGS

AF:

0.0790

AC:

273

AN:

3464

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.1

(source)

DANN

Benign

0.68

PhyloP100

-0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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