dbSNP rs8065610: PMP22:c.-592G>T (chr17-15272253-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000674868.1(PMP22):c.-592G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 152,110 control chromosomes in the GnomAD database, including 8,372 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.32 ( 8372 hom., cov: 32)

Exomes 𝑓: 0.33 ( 0 hom. )

Consequence

PMP22
ENST00000674868.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.142

Publications

6 publications found

Variant links:

COSMIC-nc: COSV70800472

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:

ENSG00000265445 (HGNC:):

ENSG00000265445 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
PMP22	ENST00000674868.1 link	c.-592G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5		ENSP00000502835.1	Q01453
PMP22	ENST00000431343.1 link	n.38G>T	non_coding_transcript_exon_variant	Exon 1 of 2	2
PMP22	ENST00000676194.1 link	n.29G>T	non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.322

AC:

49013

AN:

151980

Hom.:

8366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.240

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.326

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.371

Gnomad FIN

AF:

0.385

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.387

Gnomad OTH

AF:

0.322

GnomAD4 exome

AF:

0.333

AC:

AN:

Hom.:

Cov.:

AF XY:

0.333

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.300

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.322

AC:

49032

AN:

152098

Hom.:

8372

Cov.:

AF XY:

0.320

AC XY:

23791

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.239

AC:

9932

AN:

41494

American (AMR)

AF:

0.281

AC:

4302

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

1129

AN:

3466

East Asian (EAS)

AF:

0.115

AC:

597

AN:

5170

South Asian (SAS)

AF:

0.372

AC:

1791

AN:

4816

European-Finnish (FIN)

AF:

0.385

AC:

4070

AN:

10584

Middle Eastern (MID)

AF:

0.293

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.387

AC:

26273

AN:

67972

Other (OTH)

AF:

0.323

AC:

681

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1682

3364

5045

6727

8409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.358

Hom.:

33164

Bravo

AF:

0.309

Asia WGS

AF:

0.211

AC:

737

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.2

(source)

DANN

Benign

0.56

PhyloP100

-0.14

PromoterAI

0.029

Neutral

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over