17-15239562-G-C

Variant names:

• chr17-15239562-G-C
• rs1555565283
• NM_000304.4:c.228C>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000304.4(PMP22):​c.228C>G​(p.Ser76Arg) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S76I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.629

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript NM_000304.4 (PMP22) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-15239563-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 17-15239562-G-C is Pathogenic according to our data. Variant chr17-15239562-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448088.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4	c.228C>G	p.Ser76Arg	missense_variant	Exon 4 of 5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.228C>G	p.Ser76Arg	missense_variant	Exon 4 of 5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 27, 2017

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;.;.;D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.0029
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;.;.;.;.;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.0	M;M;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0060	.;D;D;.;D;.;.;.;D
Sift4G	Benign	0.068	T;T;T;.;T;.;.;.;T
Polyphen		1.0	D;D;D;.;.;.;.;.;.
Vest4		0.77
MutPred		0.81		Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);.;.;Gain of MoRF binding (P = 0.1032);Gain of MoRF binding (P = 0.1032);
MVP		0.76
MPC		1.2
ClinPred		0.98	D
GERP RS		-3.8
Varity_R		0.70
gMVP		0.98

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: rs1555565283; hg19: chr17-15142879;