NM_002677.5:c.*115T>C

Variant names:

• chr8-81443283-A-G
• rs6990882
• NM_002677.5:c.*115T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002677.5(PMP2):​c.*115T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 673,562 control chromosomes in the GnomAD database, including 23,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5594 hom., cov: 32)
  • Exomes 𝑓: 0.21 (18085 hom.)
• Consequence: PMP2 NM_002677.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.06
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-81443283-A-G is Benign according to our data. Variant chr8-81443283-A-G is described in ClinVar as Benign. ClinVar VariationId is 1278092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

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.*115T>C		3_prime_UTR	Exon 4 of 4	NP_002668.1	P02689
	PMP2	NM_001348381.2		c.*158T>C		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.*115T>C		3_prime_UTR	Exon 4 of 4	ENSP00000256103.2	P02689
	PMP2	ENST00000519260.1	TSL:1	c.*158T>C		3_prime_UTR	Exon 3 of 3	ENSP00000429917.1	E5RH45
	PMP2	ENST00000910617.1		c.*115T>C		3_prime_UTR	Exon 4 of 4	ENSP00000580676.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35911 AN: 151920 Hom.: 5582 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.0853

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.242

GnomAD4 exome AF: 0.212 AC: 110533 AN: 521524 Hom.: 18085 Cov.: 7 AF XY: 0.208 AC XY: 57925 AN XY: 278948

African (AFR) AF: 0.355 AC: 4679 AN: 13164

American (AMR) AF: 0.366 AC: 8374 AN: 22852

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 2513 AN: 15078

East Asian (EAS) AF: 0.751 AC: 24646 AN: 32814

South Asian (SAS) AF: 0.182 AC: 8005 AN: 43890

European-Finnish (FIN) AF: 0.0938 AC: 3542 AN: 37780

Middle Eastern (MID) AF: 0.174 AC: 518 AN: 2976

European-Non Finnish (NFE) AF: 0.161 AC: 52209 AN: 324556

Other (OTH) AF: 0.213 AC: 6047 AN: 28414

GnomAD4 genome AF: 0.237 AC: 35962 AN: 152038 Hom.: 5594 Cov.: 32 AF XY: 0.233 AC XY: 17343 AN XY: 74340

African (AFR) AF: 0.341 AC: 14160 AN: 41476

American (AMR) AF: 0.273 AC: 4177 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 536 AN: 3472

East Asian (EAS) AF: 0.736 AC: 3805 AN: 5168

South Asian (SAS) AF: 0.183 AC: 883 AN: 4820

European-Finnish (FIN) AF: 0.0853 AC: 904 AN: 10594

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10860 AN: 67906

Other (OTH) AF: 0.245 AC: 516 AN: 2104

Alfa AF: 0.191 Hom.: 1239

Bravo AF: 0.263

Asia WGS AF: 0.452 AC: 1570 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.76
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs6990882; hg19: chr8-82355518;