chr8-81443432-C-T

Variant names:

• chr8-81443432-C-T
• rs79716681
• NM_002677.5:c.365G>A

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.365G>A​(p.Gly122Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,600,130 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G122G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (63 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (63 hom.)
• Consequence: PMP2 NM_002677.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.737
• Publications: 2 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 (MetaRNN=0.0018780828).
• BP6: Variant 8-81443432-C-T is Benign according to our data. Variant chr8-81443432-C-T is described in ClinVar as Benign. ClinVar VariationId is 768248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0541 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.365G>A	p.Gly122Asp	missense	Exon 4 of 4	NP_002668.1	P02689
	PMP2	NM_001348381.2		c.*9G>A		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.365G>A	p.Gly122Asp	missense	Exon 4 of 4	ENSP00000256103.2	P02689
	PMP2	ENST00000519260.1	TSL:1	c.*9G>A		3_prime_UTR	Exon 3 of 3	ENSP00000429917.1	E5RH45
	PMP2	ENST00000910617.1		c.359G>A	p.Gly120Asp	missense	Exon 4 of 4	ENSP00000580676.1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2444 AN: 152090 Hom.: 63 Cov.: 33

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00411 AC: 992 AN: 241208 AF XY: 0.00279

Gnomad AFR exome AF: 0.0542

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000824

Gnomad OTH exome AF: 0.00223

GnomAD4 exome AF: 0.00156 AC: 2259 AN: 1447922 Hom.: 63 Cov.: 27 AF XY: 0.00137 AC XY: 987 AN XY: 720414

African (AFR) AF: 0.0559 AC: 1835 AN: 32844

American (AMR) AF: 0.00372 AC: 161 AN: 43268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25922

East Asian (EAS) AF: 0.00 AC: 0 AN: 39250

South Asian (SAS) AF: 0.0000838 AC: 7 AN: 83552

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52754

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5728

European-Non Finnish (NFE) AF: 0.0000552 AC: 61 AN: 1104734

Other (OTH) AF: 0.00314 AC: 188 AN: 59870

GnomAD4 genome AF: 0.0161 AC: 2443 AN: 152208 Hom.: 63 Cov.: 33 AF XY: 0.0153 AC XY: 1141 AN XY: 74416

African (AFR) AF: 0.0560 AC: 2325 AN: 41540

American (AMR) AF: 0.00504 AC: 77 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67980

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00548 Hom.: 53

Bravo AF: 0.0185

ESP6500AA AF: 0.0611 AC: 269

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00494 AC: 600

Asia WGS AF: 0.00203 AC: 7 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	PMP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.78
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.085	N
PhyloP100		0.74
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.088
Sift	Benign	0.98	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.32
MPC		0.13
ClinPred		0.0085	T
GERP RS		3.5
Varity_R		0.24
gMVP		0.81
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79716681; hg19: chr8-82355667;