rs371373574

Positions:

• chr17-15260656-G-C
• chr17-15260656-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000304.4(PMP22):​c.72C>G​(p.Ile24Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.774

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a transmembrane_region Helical (size 29) in uniprot entity PMP22_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000304.4
• 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.72C>G	p.Ile24Met	missense_variant	2/5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.72C>G	p.Ile24Met	missense_variant	2/5	1	NM_000304.4	ENSP00000308937	P1
	ENST00000623265.1	n.144G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 24 of the PMP22 protein (p.Ile24Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMP22-related conditions. ClinVar contains an entry for this variant (Variation ID: 1304277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMP22 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Benign	0.84
DEOGEN2	Uncertain	0.77	D;D;D;D;D;D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.88	D;.;.;.;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.2	M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	.;N;N;.;N;.;N
REVEL	Uncertain	0.55
Sift	Benign	0.11	.;T;T;.;T;.;T
Sift4G	Benign	0.093	T;T;T;.;T;.;T
Polyphen		0.99	D;D;D;.;.;.;.
Vest4		0.64
MutPred		0.66		Loss of glycosylation at S22 (P = 0.1221);Loss of glycosylation at S22 (P = 0.1221);Loss of glycosylation at S22 (P = 0.1221);Loss of glycosylation at S22 (P = 0.1221);Loss of glycosylation at S22 (P = 0.1221);Loss of glycosylation at S22 (P = 0.1221);Loss of glycosylation at S22 (P = 0.1221);
MVP		0.82
MPC		1.3
ClinPred		0.75	D
GERP RS		2.4
Varity_R		0.20
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-15163973;