chr17-15239554-G-A

Variant names:

• chr17-15239554-G-A
• rs104894618
• NM_000304.4:c.236C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000304.4(PMP22):​c.236C>T​(p.Ser79Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S79T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.88
• 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: 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000304.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-15239555-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 217236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 17-15239554-G-A is Pathogenic according to our data. Variant chr17-15239554-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1072721.Status of the report is criteria_provided_single_submitter, 1 stars.

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.236C>T	p.Ser79Phe	missense	Exon 4 of 5	NP_000295.1	Q01453
	PMP22	NM_001281455.2		c.236C>T	p.Ser79Phe	missense	Exon 4 of 5	NP_001268384.1	Q6FH25
	PMP22	NM_001281456.2		c.236C>T	p.Ser79Phe	missense	Exon 4 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.236C>T	p.Ser79Phe	missense	Exon 4 of 5	ENSP00000308937.3	Q01453
	PMP22	ENST00000494511.7	TSL:1	c.32C>T	p.Ser11Phe	missense	Exon 2 of 3	ENSP00000462782.2	J3KT36
	PMP22	ENST00000395938.7	TSL:1	c.225C>T	p.Val75Val	synonymous	Exon 4 of 5	ENSP00000379269.3	A0A6Q8PF08

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Charcot-Marie-Tooth disease, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.80
MutPred		0.79		Loss of catalytic residue at S79 (P = 0.0075)
MVP		0.95
MPC		1.4
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.57
gMVP		0.98

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: rs104894618; hg19: chr17-15142871;