17-15230689-C-T

Variant names:

• chr17-15230689-C-T
• rs1804193
• NM_000304.4:c.*228G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000304.4(PMP22):​c.*228G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0606 in 560,482 control chromosomes in the GnomAD database, including 1,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (343 hom., cov: 33)
  • Exomes 𝑓: 0.062 (963 hom.)
• Consequence: PMP22 NM_000304.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.05
• Publications: 7 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 17-15230689-C-T is Benign according to our data. Variant chr17-15230689-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 321855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000304.4. 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.*228G>A		3_prime_UTR	Exon 5 of 5	NP_000295.1	Q01453
	PMP22	NM_001281455.2		c.*228G>A		3_prime_UTR	Exon 5 of 5	NP_001268384.1	Q6FH25
	PMP22	NM_001281456.2		c.*228G>A		3_prime_UTR	Exon 5 of 5	NP_001268385.1	Q01453

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP22	ENST00000312280.9	TSL:1 MANE Select	c.*228G>A		3_prime_UTR	Exon 5 of 5	ENSP00000308937.3	Q01453
	PMP22	ENST00000395938.7	TSL:1	c.*46G>A		3_prime_UTR	Exon 5 of 5	ENSP00000379269.3	A0A6Q8PF08
	PMP22	ENST00000494511.7	TSL:1	c.*228G>A		3_prime_UTR	Exon 3 of 3	ENSP00000462782.2	J3KT36

Frequencies

GnomAD3 genomes AF: 0.0556 AC: 8464 AN: 152150 Hom.: 343 Cov.: 33

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0573

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0986

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.0612

GnomAD2 exomes AF: 0.0504 AC: 3238 AN: 64210 AF XY: 0.0496

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.0494

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.000249

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0777

Gnomad OTH exome AF: 0.0670

GnomAD4 exome AF: 0.0625 AC: 25506 AN: 408214 Hom.: 963 Cov.: 3 AF XY: 0.0600 AC XY: 12930 AN XY: 215510

African (AFR) AF: 0.0133 AC: 154 AN: 11612

American (AMR) AF: 0.0479 AC: 830 AN: 17338

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 573 AN: 12516

East Asian (EAS) AF: 0.0000732 AC: 2 AN: 27314

South Asian (SAS) AF: 0.0172 AC: 752 AN: 43612

European-Finnish (FIN) AF: 0.0987 AC: 2415 AN: 24474

Middle Eastern (MID) AF: 0.0581 AC: 102 AN: 1756

European-Non Finnish (NFE) AF: 0.0781 AC: 19210 AN: 245926

Other (OTH) AF: 0.0620 AC: 1468 AN: 23666

GnomAD4 genome AF: 0.0556 AC: 8466 AN: 152268 Hom.: 343 Cov.: 33 AF XY: 0.0559 AC XY: 4163 AN XY: 74454

African (AFR) AF: 0.0137 AC: 571 AN: 41550

American (AMR) AF: 0.0573 AC: 876 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4826

European-Finnish (FIN) AF: 0.0986 AC: 1045 AN: 10602

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0818 AC: 5560 AN: 68012

Other (OTH) AF: 0.0605 AC: 128 AN: 2114

Alfa AF: 0.0600 Hom.: 271

Bravo AF: 0.0515

Asia WGS AF: 0.00837 AC: 29 AN: 3478

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	Hereditary liability to pressure palsies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.94
PhyloP100		7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=99/1	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: rs1804193; hg19: chr17-15134006;