NM_000304.4:c.178+22A>G

Variant names:

• chr17-15259072-T-C
• rs231020
• NM_000304.4:c.178+22A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000304.4(PMP22):​c.178+22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,544,988 control chromosomes in the GnomAD database, including 224,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27480 hom., cov: 32)
  • Exomes 𝑓: 0.53 (197514 hom.)
• Consequence: PMP22 NM_000304.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.57
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-15259072-T-C is Benign according to our data. Variant chr17-15259072-T-C is described in ClinVar as Benign. ClinVar VariationId is 633487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4	c.178+22A>G		intron_variant	Intron 3 of 4	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.178+22A>G		intron_variant	Intron 3 of 4	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89832 AN: 151976 Hom.: 27423 Cov.: 32

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.701

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.592

GnomAD2 exomes AF: 0.541 AC: 134747 AN: 249120 AF XY: 0.535

Gnomad AFR exome AF: 0.762

Gnomad AMR exome AF: 0.541

Gnomad ASJ exome AF: 0.558

Gnomad EAS exome AF: 0.594

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.526

Gnomad OTH exome AF: 0.550

GnomAD4 exome AF: 0.530 AC: 738269 AN: 1392894 Hom.: 197514 Cov.: 22 AF XY: 0.530 AC XY: 369255 AN XY: 697010

African (AFR) AF: 0.764 AC: 24641 AN: 32232

American (AMR) AF: 0.548 AC: 24353 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14387 AN: 25672

East Asian (EAS) AF: 0.592 AC: 23303 AN: 39360

South Asian (SAS) AF: 0.519 AC: 43943 AN: 84646

European-Finnish (FIN) AF: 0.427 AC: 22789 AN: 53336

Middle Eastern (MID) AF: 0.609 AC: 3447 AN: 5658

European-Non Finnish (NFE) AF: 0.524 AC: 550006 AN: 1049368

Other (OTH) AF: 0.540 AC: 31400 AN: 58196

GnomAD4 genome AF: 0.591 AC: 89940 AN: 152094 Hom.: 27480 Cov.: 32 AF XY: 0.586 AC XY: 43580 AN XY: 74334

African (AFR) AF: 0.755 AC: 31327 AN: 41490

American (AMR) AF: 0.569 AC: 8709 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1945 AN: 3468

East Asian (EAS) AF: 0.594 AC: 3070 AN: 5168

South Asian (SAS) AF: 0.528 AC: 2541 AN: 4814

European-Finnish (FIN) AF: 0.423 AC: 4471 AN: 10570

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35800 AN: 67978

Other (OTH) AF: 0.595 AC: 1255 AN: 2108

Alfa AF: 0.552 Hom.: 21451

Bravo AF: 0.609

Asia WGS AF: 0.571 AC: 1983 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 30, 2019

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.20
DANN	Benign	0.53
PhyloP100		-1.6
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: rs231020; hg19: chr17-15162389;