17-15259169-C-G

Variant names:

• chr17-15259169-C-G
• rs750000952
• NM_000304.4:c.103G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000304.4(PMP22):​c.103G>C​(p.Ala35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,228 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A35T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 5 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: Ambry Genetics, Orphanet, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary neuropathy with liability to pressure palsies

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_000304.4
• PM2: Very rare variant in population databases, with high coverage

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.103G>C	p.Ala35Pro	missense	Exon 3 of 5	NP_000295.1	Q01453
	PMP22	NM_001281455.2		c.103G>C	p.Ala35Pro	missense	Exon 3 of 5	NP_001268384.1	Q6FH25
	PMP22	NM_001281456.2		c.103G>C	p.Ala35Pro	missense	Exon 3 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.103G>C	p.Ala35Pro	missense	Exon 3 of 5	ENSP00000308937.3	Q01453
	PMP22	ENST00000395938.7	TSL:1	c.103G>C	p.Ala35Pro	missense	Exon 3 of 5	ENSP00000379269.3	A0A6Q8PF08
	PMP22	ENST00000494511.7	TSL:1	c.-27+5985G>C		intron	N/A	ENSP00000462782.2	J3KT36

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251448 AF XY: 0.00

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: 6.84e-7 AC: 1 AN: 1461228 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726960

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111426

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	8.3
DANN	Benign	0.62
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.81	L
PhyloP100		-1.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.52
Sift	Benign	0.24	T
Sift4G	Benign	0.14	T
Polyphen		0.78	P
Vest4		0.45
MutPred		0.69		Loss of catalytic residue at A35 (P = 0.0264)
MVP		0.92
MPC		0.96
ClinPred		0.21	T
GERP RS		-7.1
Varity_R		0.25
gMVP		0.79

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: rs750000952; hg19: chr17-15162486;