rs201682989

Positions:

• chr17-15259199-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000304.4(PMP22):​c.79-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,604,760 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (7 hom.)
• Consequence: PMP22 NM_000304.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004068
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.857

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 17-15259199-G-A is Benign according to our data. Variant chr17-15259199-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 321862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-15259199-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMP22	NM_000304.4	c.79-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000312280.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMP22	ENST00000312280.9	c.79-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000304.4	P1

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00132 AC: 332 AN: 251320 Hom.: 3 AF XY: 0.00145 AC XY: 197 AN XY: 135814

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00461

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00118 AC: 1707 AN: 1452482 Hom.: 7 Cov.: 28 AF XY: 0.00132 AC XY: 955 AN XY: 723250

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00541

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00496

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000904

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.000867 AC: 132 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.000765 AC XY: 57 AN XY: 74466

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00131 Hom.: 1

Bravo AF: 0.000846

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PMP22: BP4, BS2 -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Dejerine-Sottas disease;C0205713:Roussy-Lévy syndrome;C0270911:Charcot-Marie-Tooth disease, type IA;C0393814:Hereditary liability to pressure palsies;C3495591:Charcot-Marie-Tooth disease type 1E;C4083008:Guillain-Barre syndrome, familial Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 07, 2021

- -

Hereditary liability to pressure palsies Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0060
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: rs201682989; hg19: chr17-15162516;