17-15239574-CGA-GAG

Variant names:

• chr17-15239574-CGA-GAG
• NM_000304.4:c.214_216delTCGinsCTC
• PMP22 p.Ser72Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5

The NM_000304.4(PMP22):c.214_216delTCGinsCTC (p.Ser72Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.82). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.S72P: Pathogenic (ClinVar VariationId 637384, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S72= (synonymous): Likely_benign (ClinVar VariationId 1186631, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.82
• 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, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hereditary neuropathy with liability to pressure palsies

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

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 46 pathogenic, 7 benign rare missense variants (OR vs. background: 31.0).; ±8 AA neighbourhood: 11 pathogenic, 0 benign (OR vs. background: 115.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.S72P: Pathogenic (ClinVar VariationId 637384, 1 star); Other variants at the same amino acid residue (not pathogenic): p.S72= (synonymous): Likely_benign (ClinVar VariationId 1186631, 2 stars)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000304.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMP22 NM_000304.4	MANE Select	c.214_216delTCGinsCTC p.Ser72Leu	missense	N/A	Prot: NP_000295.1 UniProt:
	PMP22 NM_001281455.2		c.214_216delTCGinsCTC p.Ser72Leu	missense	N/A	Prot: NP_001268384.1 UniProt:
	PMP22 NM_001281456.2		c.214_216delTCGinsCTC p.Ser72Leu	missense	N/A	Prot: NP_001268385.1 UniProt:

PMP22 NM_000304.4

MANE Select

HGVSc / HGVSpc.214_216delTCGinsCTCp.Ser72Leu

Exon rankN/A

missense

Prot: NP_000295.1UniProt: Q01453Q6FH25

PMP22 NM_001281455.2

HGVSc / HGVSpc.214_216delTCGinsCTCp.Ser72Leu

Exon rankN/A

missense

Prot: NP_001268384.1UniProt: Q6FH25Q01453

PMP22 NM_001281456.2

HGVSc / HGVSpc.214_216delTCGinsCTCp.Ser72Leu

Exon rankN/A

missense

Prot: NP_001268385.1UniProt: Q01453Q6FH25

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMP22 ENST00000312280.9	TSL:1MANE Select	c.214_216delTCGinsCTC p.Ser72Leu	missense	N/A	Prot: ENSP00000308937.3 UniProt:
	PMP22 ENST00000395938.7	TSL:1	c.203_205delTCGinsCTC p.ValAsp68AlaHis	missense	N/A	Prot: ENSP00000379269.3 UniProt:
	PMP22 ENST00000494511.7	TSL:1	c.10_12delTCGinsCTC p.Ser4Leu	missense	N/A	Prot: ENSP00000462782.2 UniProt:

PMP22 ENST00000312280.9

TSL:1MANE Select

HGVSc / HGVSpc.214_216delTCGinsCTCp.Ser72Leu

Exon rankN/A

missense

Prot: ENSP00000308937.3UniProt: Q01453

PMP22 ENST00000395938.7

TSL:1

HGVSc / HGVSpc.203_205delTCGinsCTCp.ValAsp68AlaHis

Exon rankN/A

missense

Prot: ENSP00000379269.3UniProt: A0A6Q8PF08

PMP22 ENST00000494511.7

TSL:1

HGVSc / HGVSpc.10_12delTCGinsCTCp.Ser4Leu

Exon rankN/A

missense

Prot: ENSP00000462782.2UniProt: J3KT36

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr17-15142891;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar