chr8-81443446-T-C

Variant names:

• chr8-81443446-T-C
• rs949166772
• ENST00000519260.1:c.178A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001348381.2(PMP2):​c.178A>G​(p.Met60Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,595,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M60I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMP2 NM_001348381.2 missense, splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.69
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18081135).
• BP6: Variant 8-81443446-T-C is Benign according to our data. Variant chr8-81443446-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1665370.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348381.2. 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.351A>G	p.Glu117Glu	splice_region synonymous	Exon 4 of 4	NP_002668.1	P02689
	PMP2	NM_001348381.2		c.178A>G	p.Met60Val	missense splice_region	Exon 3 of 3	NP_001335310.1	E5RH45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP2	ENST00000519260.1	TSL:1	c.178A>G	p.Met60Val	missense splice_region	Exon 3 of 3	ENSP00000429917.1	E5RH45
	PMP2	ENST00000256103.3	TSL:1 MANE Select	c.351A>G	p.Glu117Glu	splice_region synonymous	Exon 4 of 4	ENSP00000256103.2	P02689
	PMP2	ENST00000910617.1		c.345A>G	p.Glu115Glu	splice_region synonymous	Exon 4 of 4	ENSP00000580676.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240164 AF XY: 0.00000769

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000312

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: 1443806 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 718512

African (AFR) AF: 0.00 AC: 0 AN: 32822

American (AMR) AF: 0.0000233 AC: 1 AN: 42956

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101726

Other (OTH) AF: 0.00 AC: 0 AN: 59774

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

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: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.0074	T
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.7
PROVEAN	Benign	1.2	N
REVEL	Benign	0.051
Sift	Pathogenic	0.0	D
Vest4		0.27
MutPred		0.33		Gain of catalytic residue at M60 (P = 0.0373)
MVP		0.53
ClinPred		0.17	T
GERP RS		2.8
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs949166772; hg19: chr8-82355681; COSMIC: COSV107193404;