17-15230858-T-G

Variant names:

• chr17-15230858-T-G
• rs13422
• ENST00000395938.7:c.531A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 28 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 321859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395938.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP22	NM_000304.4	MANE Select	c.*59A>C		3_prime_UTR	Exon 5 of 5	NP_000295.1
	PMP22	NR_104017.2		n.637A>C		non_coding_transcript_exon	Exon 4 of 4
	PMP22	NR_104018.2		n.537A>C		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP22	ENST00000395938.7	TSL:1	c.531A>C	p.Lys177Asn	missense	Exon 5 of 5	ENSP00000379269.3
	PMP22	ENST00000312280.9	TSL:1 MANE Select	c.*59A>C		3_prime_UTR	Exon 5 of 5	ENSP00000308937.3
	PMP22	ENST00000494511.7	TSL:1	c.*59A>C		3_prime_UTR	Exon 3 of 3	ENSP00000462782.2

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

GnomAD2 exomes AF: 0.528 AC: 129815 AN: 245660 AF XY: 0.524

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 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

African (AFR) AF: 0.729 AC: 23976 AN: 32902

American (AMR) AF: 0.532 AC: 23720 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 14430 AN: 25958

East Asian (EAS) AF: 0.633 AC: 25009 AN: 39532

South Asian (SAS) AF: 0.524 AC: 44798 AN: 85564

European-Finnish (FIN) AF: 0.427 AC: 21857 AN: 51146

Middle Eastern (MID) AF: 0.601 AC: 3380 AN: 5622

European-Non Finnish (NFE) AF: 0.498 AC: 540979 AN: 1087084

Other (OTH) AF: 0.524 AC: 31087 AN: 59382

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

African (AFR) AF: 0.715 AC: 29685 AN: 41500

American (AMR) AF: 0.551 AC: 8422 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1938 AN: 3472

East Asian (EAS) AF: 0.615 AC: 3167 AN: 5148

South Asian (SAS) AF: 0.537 AC: 2584 AN: 4816

European-Finnish (FIN) AF: 0.427 AC: 4517 AN: 10568

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.501 AC: 34042 AN: 67992

Other (OTH) AF: 0.554 AC: 1169 AN: 2112

Alfa AF: 0.533 Hom.: 39081

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

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Jun 24, 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:2

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary liability to pressure palsies Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.0
DANN	Benign	0.82
PhyloP100		1.2
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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