rs377467465
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_000304.4(PMP22):c.320-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,613,198 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 1 hom. )
Consequence
PMP22
NM_000304.4 splice_region, intron
NM_000304.4 splice_region, intron
Scores
2
Splicing: ADA: 0.0001642
2
Clinical Significance
Conservation
PhyloP100: 0.420
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 17-15231084-G-A is Benign according to our data. Variant chr17-15231084-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 383080.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr17-15231084-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000217 (33/152186) while in subpopulation NFE AF= 0.00022 (15/68036). AF 95% confidence interval is 0.000135. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PMP22 | NM_000304.4 | c.320-4C>T | splice_region_variant, intron_variant | Intron 4 of 4 | ENST00000312280.9 | NP_000295.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000217 AC: 33AN: 152186Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000320 AC: 80AN: 249840Hom.: 1 AF XY: 0.000325 AC XY: 44AN XY: 135348
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GnomAD4 exome AF: 0.000229 AC: 334AN: 1461012Hom.: 1 Cov.: 33 AF XY: 0.000226 AC XY: 164AN XY: 726792
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GnomAD4 genome 0.000217 AC: 33AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74344
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Oct 01, 2016
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Dec 15, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Dec 16, 2016
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Charcot-Marie-Tooth disease Benign:1
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Molecular Genetics Laboratory, London Health Sciences Centre
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Inborn genetic diseases Benign:1
Aug 10, 2020
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Charcot-Marie-Tooth disease, type I Benign:1
Aug 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at