rs147240502
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001005242.3(PKP2):āc.1460T>Gā(p.Ile487Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,612,890 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0040 ( 5 hom., cov: 32)
Exomes š: 0.0041 ( 28 hom. )
Consequence
PKP2
NM_001005242.3 missense
NM_001005242.3 missense
Scores
5
6
5
Clinical Significance
Conservation
PhyloP100: 7.83
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0121154785).
BP6
?
Variant 12-32841124-A-C is Benign according to our data. Variant chr12-32841124-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 45035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32841124-A-C is described in Lovd as [Benign]. Variant chr12-32841124-A-C is described in Lovd as [Pathogenic]. Variant chr12-32841124-A-C is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00397 (604/152244) while in subpopulation NFE AF= 0.00429 (292/68020). AF 95% confidence interval is 0.00389. There are 5 homozygotes in gnomad4. There are 354 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 604 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1460T>G | p.Ile487Ser | missense_variant | 6/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1460T>G | p.Ile487Ser | missense_variant | 6/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00397 AC: 604AN: 152126Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00480 AC: 1207AN: 251382Hom.: 4 AF XY: 0.00482 AC XY: 655AN XY: 135842
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GnomAD4 exome AF: 0.00411 AC: 6000AN: 1460646Hom.: 28 Cov.: 30 AF XY: 0.00406 AC XY: 2948AN XY: 726754
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GnomAD4 genome ? AF: 0.00397 AC: 604AN: 152244Hom.: 5 Cov.: 32 AF XY: 0.00476 AC XY: 354AN XY: 74432
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Blueprint Genetics | May 27, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 08, 2015 | p.Ile531Ser in exon 7 of PKP2: This variant is not expected to have clinical sig nificance because it has been identified in 2.6% (170/6614) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs147240502). - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2013 | 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. - |
Arrhythmogenic right ventricular dysplasia 9 Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 01, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PKP2: BP4, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 16, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 12, 2016 | Variant summary: The PKP2 c.1592T>G (p.Ile531Ser) variant causes a missense change with 3/3 in silico tools (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a damaging outcome for this variant. This variant was found in 867/136406 control chromosomes (2 homozygotes) at a frequency of 0.006356, which is approximately 15 times the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0004301), suggesting this variant is likely a benign polymorphism. In addition, multiple publications report the variant to co-occur with other potentially pathogenic variants. In the few small pedigrees published, the variant did not segregate within families, leading authors to conclude that this variant could be modulating the effect of another variant or this variant could have low penetrance. Furthermore, functional studies support the variant to have comparable to wild-type function. In addition, multiple reputable clinical diagnostic laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 13, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 07, 2016 | - - |
Arrhythmogenic right ventricular cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Family history of cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Apr 18, 2018 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2015 | This alteration is classified as 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
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.51
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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Score
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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