rs774831750

Variant names:

• chr17-15231062-G-A
• rs774831750
• NM_000304.4:c.338C>T
• PMP22 p.Ala113Val

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000304.4(PMP22):​c.338C>T​(p.Ala113Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A113T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.80
• Publications: 0 publications found

Genes affected

PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PMP22 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 1A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary neuropathy with liability to pressure palsies

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 1E

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000304.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000304.4. 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
	PMP22	NM_000304.4	MANE Select	c.338C>T	p.Ala113Val	missense	Exon 5 of 5	NP_000295.1	Q01453
	PMP22	NM_001281455.2		c.338C>T	p.Ala113Val	missense	Exon 5 of 5	NP_001268384.1	Q6FH25
	PMP22	NM_001281456.2		c.338C>T	p.Ala113Val	missense	Exon 5 of 5	NP_001268385.1	Q01453

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMP22	ENST00000312280.9	TSL:1 MANE Select	c.338C>T	p.Ala113Val	missense	Exon 5 of 5	ENSP00000308937.3	Q01453
	PMP22	ENST00000494511.7	TSL:1	c.134C>T	p.Ala45Val	missense	Exon 3 of 3	ENSP00000462782.2	J3KT36
	PMP22	ENST00000395938.7	TSL:1	c.327C>T	p.Cys109Cys	synonymous	Exon 5 of 5	ENSP00000379269.3	A0A6Q8PF08

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250652 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461612 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease, type I (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.30
gMVP		0.87

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs774831750;

hg19: chr17-15134379;