ENST00000395938.7:c.645C>T

Variant names:

• chr17-15230744-G-A
• rs117277951
• ENST00000395938.7:c.645C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000395938.7(PMP22):​c.645C>T​(p.Ser215Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 646,408 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: PMP22 ENST00000395938.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.728
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 17-15230744-G-A is Benign according to our data. Variant chr17-15230744-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 321857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.728 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000552 (84/152286) while in subpopulation EAS AF = 0.0129 (67/5176). AF 95% confidence interval is 0.0105. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4	c.*173C>T		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.*173C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00164 AC: 157 AN: 95700 AF XY: 0.00173

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0151

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000886

Gnomad OTH exome AF: 0.000730

GnomAD4 exome AF: 0.00106 AC: 522 AN: 494122 Hom.: 4 Cov.: 6 AF XY: 0.000942 AC XY: 248 AN XY: 263390

African (AFR) AF: 0.00 AC: 0 AN: 13336

American (AMR) AF: 0.0000444 AC: 1 AN: 22528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14838

East Asian (EAS) AF: 0.0149 AC: 476 AN: 32032

South Asian (SAS) AF: 0.000182 AC: 9 AN: 49332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2148

European-Non Finnish (NFE) AF: 0.0000732 AC: 22 AN: 300414

Other (OTH) AF: 0.000505 AC: 14 AN: 27710

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000618 AC XY: 46 AN XY: 74470

African (AFR) AF: 0.0000962 AC: 4 AN: 41568

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0129 AC: 67 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000233 Hom.: 0

Bravo AF: 0.000827

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jan 23, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary liability to pressure palsies Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Charcot-Marie-Tooth disease, type I Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.54
CADD	Benign	1.0
DANN	Benign	0.58
PhyloP100		0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism

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: rs117277951; hg19: chr17-15134061;