rs74361095

Variant names:

• chr17-15231004-G-A
• rs74361095
• ENST00000395938.7:c.385C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000395938.7(PMP22):​c.385C>T​(p.Arg129Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,112 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R129Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0069 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (17 hom.)
• Consequence: PMP22 ENST00000395938.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.755
• Publications: 2 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: Ambry Genetics, Orphanet, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary neuropathy with liability to pressure palsies

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 1E

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, 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 -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 3 uncertain in ENST00000395938.7
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 17-15231004-G-A is Benign according to our data. Variant chr17-15231004-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 378379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00688 (1048/152318) while in subpopulation AFR AF = 0.0241 (1002/41570). AF 95% confidence interval is 0.0229. There are 19 homozygotes in GnomAd4. There are 517 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1048 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP22	NM_000304.4	MANE Select	c.396C>T	p.Tyr132Tyr	synonymous	Exon 5 of 5	NP_000295.1	Q01453
	PMP22	NM_001281455.2		c.396C>T	p.Tyr132Tyr	synonymous	Exon 5 of 5	NP_001268384.1	Q6FH25
	PMP22	NM_001281456.2		c.396C>T	p.Tyr132Tyr	synonymous	Exon 5 of 5	NP_001268385.1	Q01453

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP22	ENST00000395938.7	TSL:1	c.385C>T	p.Arg129Trp	missense	Exon 5 of 5	ENSP00000379269.3	A0A6Q8PF08
	PMP22	ENST00000312280.9	TSL:1 MANE Select	c.396C>T	p.Tyr132Tyr	synonymous	Exon 5 of 5	ENSP00000308937.3	Q01453
	PMP22	ENST00000494511.7	TSL:1	c.192C>T	p.Tyr64Tyr	synonymous	Exon 3 of 3	ENSP00000462782.2	J3KT36

Frequencies

GnomAD3 genomes AF: 0.00689 AC: 1049 AN: 152200 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00180 AC: 452 AN: 251308 AF XY: 0.00133

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000648 AC: 947 AN: 1461794 Hom.: 17 Cov.: 33 AF XY: 0.000540 AC XY: 393 AN XY: 727210

African (AFR) AF: 0.0235 AC: 787 AN: 33476

American (AMR) AF: 0.00114 AC: 51 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111944

Other (OTH) AF: 0.00118 AC: 71 AN: 60394

GnomAD4 genome AF: 0.00688 AC: 1048 AN: 152318 Hom.: 19 Cov.: 33 AF XY: 0.00694 AC XY: 517 AN XY: 74470

African (AFR) AF: 0.0241 AC: 1002 AN: 41570

American (AMR) AF: 0.00203 AC: 31 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00541 Hom.: 7

Bravo AF: 0.00768

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease, type I (1)
-	-	1	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 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.38
DANN	Benign	0.63
PhyloP100		-0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=88/12	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: rs74361095; hg19: chr17-15134321; COSMIC: COSV100397036; COSMIC: COSV100397036;