17-15230689-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000304.4(PMP22):c.*228G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0606 in 560,482 control chromosomes in the GnomAD database, including 1,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 343 hom., cov: 33)

Exomes 𝑓: 0.062 ( 963 hom. )

Consequence

PMP22
NM_000304.4 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.05

Publications

7 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 17-15230689-C-T is Benign according to our data. Variant chr17-15230689-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 321855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4 link	c.*228G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9 link	c.*228G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_000304.4	ENSP00000308937.3		Q01453

Frequencies

GnomAD3 genomes

AF:

0.0556

AC:

8464

AN:

152150

Hom.:

343

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0573

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0986

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0817

Gnomad OTH

AF:

0.0612

GnomAD2 exomes

AF:

0.0504

AC:

3238

AN:

64210

AF XY:

0.0496

show subpopulations

Gnomad AFR exome

AF:

0.0141

Gnomad AMR exome

AF:

0.0494

Gnomad ASJ exome

AF:

0.0466

Gnomad EAS exome

AF:

0.000249

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.0777

Gnomad OTH exome

AF:

0.0670

GnomAD4 exome

AF:

0.0625

AC:

25506

AN:

408214

Hom.:

963

Cov.:

AF XY:

0.0600

AC XY:

12930

AN XY:

215510

show subpopulations

African (AFR)

AF:

0.0133

AC:

154

AN:

11612

American (AMR)

AF:

0.0479

AC:

830

AN:

17338

Ashkenazi Jewish (ASJ)

AF:

0.0458

AC:

573

AN:

12516

East Asian (EAS)

AF:

0.0000732

AC:

AN:

27314

South Asian (SAS)

AF:

0.0172

AC:

752

AN:

43612

European-Finnish (FIN)

AF:

0.0987

AC:

2415

AN:

24474

Middle Eastern (MID)

AF:

0.0581

AC:

102

AN:

1756

European-Non Finnish (NFE)

AF:

0.0781

AC:

19210

AN:

245926

Other (OTH)

AF:

0.0620

AC:

1468

AN:

23666

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1159

2318

3476

4635

5794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0556

AC:

8466

AN:

152268

Hom.:

343

Cov.:

AF XY:

0.0559

AC XY:

4163

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0137

AC:

571

AN:

41550

American (AMR)

AF:

0.0573

AC:

876

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

169

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.0153

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0986

AC:

1045

AN:

10602

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0818

AC:

5560

AN:

68012

Other (OTH)

AF:

0.0605

AC:

128

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

392

785

1177

1570

1962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0600

Hom.:

271

Bravo

AF:

0.0515

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary liability to pressure palsies

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease, type I

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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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17-15230689-C-T

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