1-201283717-G-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP7BS1_Supporting
The NM_001005337.3(PKP1):c.15G>T(p.Pro5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,612 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000057 ( 1 hom. )
Consequence
PKP1
NM_001005337.3 synonymous
NM_001005337.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.237
Genes affected
PKP1 (HGNC:9023): (plakophilin 1) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This protein may be involved in molecular recruitment and stabilization during desmosome formation. Mutations in this gene have been associated with the ectodermal dysplasia/skin fragility syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP7
Synonymous conserved (PhyloP=-0.237 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000568 (83/1461406) while in subpopulation EAS AF= 0.00204 (81/39670). AF 95% confidence interval is 0.00168. There are 1 homozygotes in gnomad4_exome. There are 42 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKP1 | NM_001005337.3 | c.15G>T | p.Pro5= | synonymous_variant | 1/14 | ENST00000367324.8 | NP_001005337.1 | |
| PKP1 | NM_000299.4 | c.15G>T | p.Pro5= | synonymous_variant | 1/15 | NP_000290.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PKP1 | ENST00000367324.8 | c.15G>T | p.Pro5= | synonymous_variant | 1/14 | 1 | NM_001005337.3 | ENSP00000356293 | P1 | |
| PKP1 | ENST00000263946.7 | c.15G>T | p.Pro5= | synonymous_variant | 1/15 | 5 | ENSP00000263946 | |||
| PKP1 | ENST00000352845.3 | c.15G>T | p.Pro5= | synonymous_variant | 1/14 | 5 | ENSP00000295597 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250298Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135402
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GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461406Hom.: 1 Cov.: 32 AF XY: 0.0000578 AC XY: 42AN XY: 726988
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GnomAD4 genome 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Epidermolysis bullosa simplex due to plakophilin deficiency Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at