8-81443403-C-A

Variant names:

• chr8-81443403-C-A
• rs546518432
• NM_002677.5:c.394G>T

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.394G>T​(p.Val132Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,596,066 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. V132A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PMP2 NM_002677.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.79
• 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=0.23123893).

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.394G>T	p.Val132Phe	missense	Exon 4 of 4	NP_002668.1	P02689
	PMP2	NM_001348381.2		c.*38G>T		3_prime_UTR	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.394G>T	p.Val132Phe	missense	Exon 4 of 4	ENSP00000256103.2	P02689
	PMP2	ENST00000519260.1	TSL:1	c.*38G>T		3_prime_UTR	Exon 3 of 3	ENSP00000429917.1	E5RH45
	PMP2	ENST00000910617.1		c.388G>T	p.Val130Phe	missense	Exon 4 of 4	ENSP00000580676.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443984 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 718532

African (AFR) AF: 0.00 AC: 0 AN: 32694

American (AMR) AF: 0.00 AC: 0 AN: 42748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25848

East Asian (EAS) AF: 0.00 AC: 0 AN: 39210

South Asian (SAS) AF: 0.00 AC: 0 AN: 82850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102412

Other (OTH) AF: 0.00 AC: 0 AN: 59734

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74276

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		2.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.58	P
Vest4		0.41
MutPred		0.50		Loss of disorder (P = 0.1174)
MVP		0.59
MPC		0.26
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.61
gMVP		0.89
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs546518432; hg19: chr8-82355638;