19-40394272-TTCCTCCTCCTCC-TTCCTCCTCCTCCTCCTCC
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_181882.3(PRX):c.4079_4080insGGAGGA(p.Glu1360_Glu1361dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,605,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
PRX
NM_181882.3 inframe_insertion
NM_181882.3 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.16
Genes affected
PRX (HGNC:13797): (periaxin) This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 19-40394272-T-TTCCTCC is Benign according to our data. Variant chr19-40394272-T-TTCCTCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1052678.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.4079_4080insGGAGGA | p.Glu1360_Glu1361dup | inframe_insertion | 7/7 | ENST00000324001.8 | NP_870998.2 | |
PRX | NM_001411127.1 | c.4364_4365insGGAGGA | p.Glu1455_Glu1456dup | inframe_insertion | 7/7 | NP_001398056.1 | ||
PRX | XM_017027047.2 | c.3977_3978insGGAGGA | p.Glu1326_Glu1327dup | inframe_insertion | 4/4 | XP_016882536.1 | ||
PRX | NM_020956.2 | c.*4284_*4285insGGAGGA | 3_prime_UTR_variant | 6/6 | NP_066007.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRX | ENST00000324001.8 | c.4079_4080insGGAGGA | p.Glu1360_Glu1361dup | inframe_insertion | 7/7 | 1 | NM_181882.3 | ENSP00000326018 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000661 AC: 1AN: 151214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000137 AC: 2AN: 145830Hom.: 0 AF XY: 0.0000128 AC XY: 1AN XY: 78150
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GnomAD4 exome AF: 0.00000413 AC: 6AN: 1453816Hom.: 0 Cov.: 29 AF XY: 0.00000415 AC XY: 3AN XY: 722810
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GnomAD4 genome AF: 0.00000661 AC: 1AN: 151214Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73800
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 22, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with PRX-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant, c.4074_4079dup, results in the insertion of 2 amino acid(s) of the PRX protein (p.Glu1360_Glu1361dup), but otherwise preserves the integrity of the reading frame. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2023 | 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. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at