rs143782040
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001005242.3(PKP2):āc.1509T>Cā(p.Asn503=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.00019 ( 0 hom., cov: 32)
Exomes š: 0.00015 ( 0 hom. )
Consequence
PKP2
NM_001005242.3 synonymous
NM_001005242.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.329
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
?
Variant 12-32841075-A-G is Benign according to our data. Variant chr12-32841075-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.329 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000191 (29/152170) while in subpopulation EAS AF= 0.00542 (28/5170). AF 95% confidence interval is 0.00385. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 29 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1509T>C | p.Asn503= | synonymous_variant | 6/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1509T>C | p.Asn503= | synonymous_variant | 6/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152052Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000525 AC: 132AN: 251308Hom.: 1 AF XY: 0.000471 AC XY: 64AN XY: 135814
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GnomAD4 exome AF: 0.000147 AC: 215AN: 1461666Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 81AN XY: 727156
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GnomAD4 genome ? AF: 0.000191 AC: 29AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74396
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 02, 2014 | p.Asn547Asn in exon 7 of PKP2: This variant is not expected to have clinical sig nificance because it has been identified in 1.0% (6/572) of East Asian chromosom es by the 1000 Genomes Project (dbSNP rs143782040). - |
Arrhythmogenic right ventricular dysplasia 9 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 27, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Arrhythmogenic right ventricular cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 09, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2016 | 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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Name
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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