17-15230388-CAG-C

Variant names:

• chr17-15230388-CAG-C
• rs71699667
• NM_000304.4:c.*527_*528delCT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000304.4(PMP22):​c.*527_*528delCT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 160,766 control chromosomes in the GnomAD database, including 10,480 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (9823 hom., cov: 0)
  • Exomes 𝑓: 0.36 (657 hom.)
• Consequence: PMP22 NM_000304.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.618
• Publications: 3 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 -10 ACMG points.

• BP6: Variant 17-15230388-CAG-C is Benign according to our data. Variant chr17-15230388-CAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 321853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4	c.*527_*528delCT		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	c.*527_*528delCT		3_prime_UTR_variant	Exon 5 of 5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53096 AN: 151874 Hom.: 9821 Cov.: 0

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.357 AC: 3136 AN: 8774 Hom.: 657 AF XY: 0.360 AC XY: 1673 AN XY: 4648

African (AFR) AF: 0.135 AC: 7 AN: 52

American (AMR) AF: 0.378 AC: 624 AN: 1650

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 33 AN: 76

East Asian (EAS) AF: 0.228 AC: 106 AN: 464

South Asian (SAS) AF: 0.346 AC: 333 AN: 962

European-Finnish (FIN) AF: 0.343 AC: 181 AN: 528

Middle Eastern (MID) AF: 0.357 AC: 5 AN: 14

European-Non Finnish (NFE) AF: 0.371 AC: 1744 AN: 4696

Other (OTH) AF: 0.310 AC: 103 AN: 332

GnomAD4 genome AF: 0.349 AC: 53108 AN: 151992 Hom.: 9823 Cov.: 0 AF XY: 0.350 AC XY: 26040 AN XY: 74308

African (AFR) AF: 0.210 AC: 8733 AN: 41494

American (AMR) AF: 0.411 AC: 6280 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1417 AN: 3470

East Asian (EAS) AF: 0.284 AC: 1464 AN: 5152

South Asian (SAS) AF: 0.375 AC: 1803 AN: 4810

European-Finnish (FIN) AF: 0.388 AC: 4094 AN: 10554

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27908 AN: 67938

Other (OTH) AF: 0.357 AC: 753 AN: 2112

Alfa AF: 0.374 Hom.: 1325

Bravo AF: 0.345

Asia WGS AF: 0.319 AC: 1109 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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
PhyloP100		0.62
Mutation Taster		=100/0	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: rs71699667; hg19: chr17-15133705; COSMIC: COSV56601170; COSMIC: COSV56601170;