rs104894620

Positions:

• chr17-15239584-A-C
• chr17-15239584-A-G
• chr17-15239584-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The ENST00000494511.7(PMP22):​c.2T>G​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 ENST00000494511.7 start_lost
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.16

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000494511.7 (PMP22) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 531685
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMP22	NM_000304.4	c.206T>G	p.Met69Arg	missense_variant	4/5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.206T>G	p.Met69Arg	missense_variant	4/5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;.;.;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;.;.;.;.;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.4	.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;D;D;.;D;.;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;.;D;.;.;.;D
Polyphen		1.0	D;D;D;.;.;.;.;.;.
Vest4		0.98
MutPred		0.91		Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);.;.;Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894620; hg19: chr17-15142901;