NM_000304.4:c.319+33C>T

Variant names:

Variant summary

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

The NM_000304.4(PMP22):c.319+33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 1,612,302 control chromosomes in the GnomAD database, including 6,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 484 hom., cov: 33)

Exomes 𝑓: 0.085 ( 5905 hom. )

Consequence

PMP22
NM_000304.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.519

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 1A
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
hereditary neuropathy with liability to pressure palsies
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
Charcot-Marie-Tooth disease type 1E
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PMP22 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 (MetaRNN=0.0014778078).

BP6

Variant 17-15239438-G-A is Benign according to our data. Variant chr17-15239438-G-A is described in ClinVar as Benign. ClinVar VariationId is 633490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4 link	c.319+33C>T		intron_variant	Intron 4 of 4	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9 link	c.319+33C>T		intron_variant	Intron 4 of 4	1	NM_000304.4	ENSP00000308937.3		Q01453

Frequencies

GnomAD3 genomes

AF:

0.0652

AC:

9912

AN:

152118

Hom.:

484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0193

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0554

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.149

Gnomad FIN

AF:

0.0372

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0824

Gnomad OTH

AF:

0.0746

GnomAD2 exomes

AF:

0.0847

AC:

21288

AN:

251458

AF XY:

0.0898

show subpopulations

Gnomad AFR exome

AF:

0.0183

Gnomad AMR exome

AF:

0.0418

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.175

Gnomad FIN exome

AF:

0.0428

Gnomad NFE exome

AF:

0.0827

Gnomad OTH exome

AF:

0.0884

GnomAD4 exome

AF:

0.0846

AC:

123526

AN:

1460066

Hom.:

5905

Cov.:

AF XY:

0.0867

AC XY:

63010

AN XY:

726424

show subpopulations

African (AFR)

AF:

0.0182

AC:

608

AN:

33462

American (AMR)

AF:

0.0438

AC:

1961

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

2844

AN:

26120

East Asian (EAS)

AF:

0.156

AC:

6184

AN:

39684

South Asian (SAS)

AF:

0.140

AC:

12112

AN:

86214

European-Finnish (FIN)

AF:

0.0420

AC:

2243

AN:

53418

Middle Eastern (MID)

AF:

0.0922

AC:

532

AN:

5768

European-Non Finnish (NFE)

AF:

0.0828

AC:

91911

AN:

1110372

Other (OTH)

AF:

0.0851

AC:

5131

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

5789

11578

17368

23157

28946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3474

6948

10422

13896

17370

<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:

0.0651

AC:

9910

AN:

152236

Hom.:

484

Cov.:

AF XY:

0.0633

AC XY:

4709

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0195

AC:

808

AN:

41540

American (AMR)

AF:

0.0553

AC:

846

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

427

AN:

3470

East Asian (EAS)

AF:

0.173

AC:

893

AN:

5170

South Asian (SAS)

AF:

0.149

AC:

716

AN:

4816

European-Finnish (FIN)

AF:

0.0372

AC:

394

AN:

10598

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0824

AC:

5603

AN:

68024

Other (OTH)

AF:

0.0734

AC:

155

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

477

953

1430

1906

2383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<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:

0.0620

Hom.:

189

Bravo

AF:

0.0639

TwinsUK

AF:

0.0790

AC:

293

ALSPAC

AF:

0.0856

AC:

330

ESP6500AA

AF:

0.0191

AC:

ESP6500EA

AF:

0.0887

AC:

763

ExAC

AF:

0.0842

AC:

10228

Asia WGS

AF:

0.148

AC:

511

AN:

3478

EpiCase

AF:

0.0845

EpiControl

AF:

0.0855

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 26, 2018

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

- -

Charcot-Marie-Tooth disease, type I

Benign:1

Jan 30, 2019

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

0.88

(source)

DANN

Benign

0.68

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0015

PhyloP100

-0.52

Sift4G

Uncertain

0.043

Vest4

0.079

GERP RS

-2.2

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over