8-81443444-C-G

Variant names:

• chr8-81443444-C-G
• rs202025915
• NM_002677.5:c.353G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002677.5(PMP2):​c.353G>C​(p.Cys118Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,443,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. C118Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMP2 NM_002677.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12
• Publications: 0 publications found

Genes affected

PMP2 (HGNC:9117): (peripheral myelin protein 2) The protein encoded by this gene localizes to myelin sheaths of the peripheral nervous system. The encoded protein can bind both the membrane layers of the sheaths and monomeric lipids, and is thought to provide stability to the sheath. A defect in this gene was shown to be a cause of dominant demyelinating CMT neuropathy. [provided by RefSeq, Jan 2017]

PMP2 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease, demyelinating, type 1G

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ENSG00000253374 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22948357).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002677.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP2	NM_002677.5	MANE Select	c.353G>C	p.Cys118Ser	missense	Exon 4 of 4	NP_002668.1	P02689
	PMP2	NM_001348381.2		c.180G>C	p.Met60Ile	missense	Exon 3 of 3	NP_001335310.1	E5RH45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP2	ENST00000256103.3	TSL:1 MANE Select	c.353G>C	p.Cys118Ser	missense	Exon 4 of 4	ENSP00000256103.2	P02689
	PMP2	ENST00000519260.1	TSL:1	c.180G>C	p.Met60Ile	missense	Exon 3 of 3	ENSP00000429917.1	E5RH45
	PMP2	ENST00000910617.1		c.347G>C	p.Cys116Ser	missense	Exon 4 of 4	ENSP00000580676.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240124 AF XY: 0.00000768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1443936 Hom.: 0 Cov.: 26 AF XY: 0.00000278 AC XY: 2 AN XY: 718508

African (AFR) AF: 0.00 AC: 0 AN: 32816

American (AMR) AF: 0.00 AC: 0 AN: 42918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39238

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 83038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101950

Other (OTH) AF: 0.00 AC: 0 AN: 59762

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.18
Sift	Benign	0.20	T
Sift4G	Benign	0.15	T
Polyphen		0.055	B
Vest4		0.35
MutPred		0.67		Gain of disorder (P = 0.0101)
MVP		0.56
MPC		0.14
ClinPred		0.37	T
GERP RS		5.3
Varity_R		0.87
gMVP		0.91
Mutation Taster		=35/65	disease causing

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: rs202025915; hg19: chr8-82355679;