NM_000304.4:c.185T>C

Variant names:

• chr17-15239605-A-G
• rs756046682
• NM_000304.4:c.185T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000304.4(PMP22):​c.185T>C​(p.Leu62Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L62R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.16
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000304.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP22	NM_000304.4	MANE Select	c.185T>C	p.Leu62Pro	missense	Exon 4 of 5	NP_000295.1
	PMP22	NM_001281455.2		c.185T>C	p.Leu62Pro	missense	Exon 4 of 5	NP_001268384.1
	PMP22	NM_001281456.2		c.185T>C	p.Leu62Pro	missense	Exon 4 of 5	NP_001268385.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP22	ENST00000312280.9	TSL:1 MANE Select	c.185T>C	p.Leu62Pro	missense	Exon 4 of 5	ENSP00000308937.3
	PMP22	ENST00000494511.7	TSL:1	c.-20T>C		5_prime_UTR	Exon 2 of 3	ENSP00000462782.2
	PMP22	ENST00000395938.7	TSL:1	c.179-5T>C		splice_region intron	N/A	ENSP00000379269.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.81		Gain of disorder (P = 0.007)
MVP		0.95
MPC		1.7
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.97

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: rs756046682; hg19: chr17-15142922;