17-15230858-T-G

Position:

• chr17-15230858-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000395938.7(PMP22):​c.531A>C​(p.Lys177Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 1,583,870 control chromosomes in the GnomAD database, including 212,586 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25172 hom., cov: 33)
  • Exomes 𝑓: 0.51 (187414 hom.)
• Consequence: PMP22 ENST00000395938.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.18

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 17-15230858-T-G is Benign according to our data. Variant chr17-15230858-T-G is described in ClinVar as [Benign]. Clinvar id is 321859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-15230858-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMP22	NM_000304.4	c.*59A>C		3_prime_UTR_variant	5/5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280	c.*59A>C		3_prime_UTR_variant	5/5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86180 AN: 151982 Hom.: 25125 Cov.: 33

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.550

GnomAD3 exomes AF: 0.528 AC: 129815 AN: 245660 Hom.: 34867 AF XY: 0.524 AC XY: 69883 AN XY: 133348

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.556

Gnomad EAS exome AF: 0.610

Gnomad SAS exome AF: 0.523

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.504

Gnomad OTH exome AF: 0.529

GnomAD4 exome AF: 0.509 AC: 729236 AN: 1431770 Hom.: 187414 Cov.: 25 AF XY: 0.510 AC XY: 363677 AN XY: 713456

Gnomad4 AFR exome AF: 0.729

Gnomad4 AMR exome AF: 0.532

Gnomad4 ASJ exome AF: 0.556

Gnomad4 EAS exome AF: 0.633

Gnomad4 SAS exome AF: 0.524

Gnomad4 FIN exome AF: 0.427

Gnomad4 NFE exome AF: 0.498

Gnomad4 OTH exome AF: 0.524

GnomAD4 genome AF: 0.567 AC: 86280 AN: 152100 Hom.: 25172 Cov.: 33 AF XY: 0.564 AC XY: 41925 AN XY: 74340

Gnomad4 AFR AF: 0.715

Gnomad4 AMR AF: 0.551

Gnomad4 ASJ AF: 0.558

Gnomad4 EAS AF: 0.615

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.427

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.554

Alfa AF: 0.518 Hom.: 27592

Bravo AF: 0.583

Asia WGS AF: 0.581 AC: 2016 AN: 3478

EpiCase AF: 0.513

EpiControl AF: 0.509

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Charcot-Marie-Tooth disease, type I Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jan 30, 2019	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Hereditary liability to pressure palsies Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.0
DANN	Benign	0.82

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

LitVar

Other links and lift over

dbSNP: rs13422; hg19: chr17-15134175; COSMIC: COSV56601449; COSMIC: COSV56601449;