rs560220280
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PP3_StrongBS1_SupportingBS2_Supporting
The NM_001005242.3(PKP2):c.713C>T(p.Pro238Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,614,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P238P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
PKP2
NM_001005242.3 missense
NM_001005242.3 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 5.40
Genes affected
PKP2 (HGNC:9024): (plakophilin 2) 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 gene may regulate the signaling activity of beta-catenin and is required to maintain transcription of genes that control intracellular calcium cycling including ryanodine receptor 2, ankyrin-B, triadin, and calcium channel, voltage-dependent, L type, alpha 1C. Mutations in this gene are associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy, Brugada Syndrome, and Idiopathic Ventricular Fibrillation. A processed pseudogene with high similarity to this gene has been mapped to chromosome 12p13. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.945
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000547 (80/1461868) while in subpopulation SAS AF= 0.000777 (67/86254). AF 95% confidence interval is 0.000627. There are 0 homozygotes in gnomad4_exome. There are 56 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKP2 | NM_001005242.3 | c.713C>T | p.Pro238Leu | missense_variant | 3/13 | ENST00000340811.9 | NP_001005242.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PKP2 | ENST00000340811.9 | c.713C>T | p.Pro238Leu | missense_variant | 3/13 | 1 | NM_001005242.3 | ENSP00000342800 | P1 |
Frequencies
GnomAD3 genomes 0.0000328 AC: 5AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251276Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135826
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GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461868Hom.: 0 Cov.: 33 AF XY: 0.0000770 AC XY: 56AN XY: 727232
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GnomAD4 genome 0.0000328 AC: 5AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74506
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 23, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 238 of the PKP2 protein (p.Pro238Leu). This variant is present in population databases (rs560220280, gnomAD 0.04%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 20400443). ClinVar contains an entry for this variant (Variation ID: 406544). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 13, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
not provided Uncertain:3
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2022 | Reported in an individual with ARVC (Fressart et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31402444, 20400443) - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 25, 2023 | This missense variant replaces proline with leucine at codon 238 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443), in at least one individual affected with dilated cardiomyopathy (PMID: 25163546), and in two individuals affected with or suspected to be affected with an unspecified cardiomyopathy (PMID: 30847666, 37477868). This variant has been identified in 11/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | This missense variant replaces proline with leucine at codon 238 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443), in at least one individual affected with dilated cardiomyopathy (PMID: 25163546), and in two individuals affected with or suspected to be affected with an unspecified cardiomyopathy (PMID: 30847666, 37477868). This variant has been identified in 11/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2021 | The p.P238L variant (also known as c.713C>T), located in coding exon 3 of the PKP2 gene, results from a C to T substitution at nucleotide position 713. The proline at codon 238 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort, as well as a cardiac genetic testing cohort in an individual with another cardiac-related alteration identified (Fressart V et al. Europace, 2010 Jun;12:861-8; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of glycosylation at P238 (P = 0.0575);Loss of glycosylation at P238 (P = 0.0575);
MVP
MPC
0.60
ClinPred
D
GERP RS
Varity_R
gMVP
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