rs1555143134
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001005242.3(PKP2):c.1593_1596dupGATG(p.Arg533AspfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,258 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PKP2
NM_001005242.3 frameshift
NM_001005242.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.08
Publications
0 publications found
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]
PKP2 Gene-Disease associations (from GenCC):
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- arrhythmogenic right ventricular dysplasia 9Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- left ventricular noncompactionInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Brugada syndromeInheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
- Brugada syndrome 1Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- catecholaminergic polymorphic ventricular tachycardiaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- dilated cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-32824122-T-TCATC is Pathogenic according to our data. Variant chr12-32824122-T-TCATC is described in ClinVar as Pathogenic. ClinVar VariationId is 406551.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001005242.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PKP2 | NM_001005242.3 | MANE Select | c.1593_1596dupGATG | p.Arg533AspfsTer5 | frameshift | Exon 7 of 13 | NP_001005242.2 | Q99959-2 | |
| PKP2 | NM_004572.4 | c.1725_1728dupGATG | p.Arg577AspfsTer5 | frameshift | Exon 8 of 14 | NP_004563.2 | Q99959-1 | ||
| PKP2 | NM_001407155.1 | c.1593_1596dupGATG | p.Arg533AspfsTer5 | frameshift | Exon 7 of 12 | NP_001394084.1 | A0A8V8TPU9 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PKP2 | ENST00000340811.9 | TSL:1 MANE Select | c.1593_1596dupGATG | p.Arg533AspfsTer5 | frameshift | Exon 7 of 13 | ENSP00000342800.5 | Q99959-2 | |
| PKP2 | ENST00000070846.11 | TSL:1 | c.1725_1728dupGATG | p.Arg577AspfsTer5 | frameshift | Exon 8 of 14 | ENSP00000070846.6 | Q99959-1 | |
| PKP2 | ENST00000700559.2 | c.1593_1596dupGATG | p.Arg533AspfsTer5 | frameshift | Exon 7 of 12 | ENSP00000515065.2 | A0A8V8TPU9 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461258Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726978 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1461258
Hom.:
Cov.:
29
AF XY:
AC XY:
1
AN XY:
726978
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33470
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
2
AN:
39694
South Asian (SAS)
AF:
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
AC:
0
AN:
53184
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111652
Other (OTH)
AF:
AC:
0
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
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2
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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8
10
<30
30-35
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Arrhythmogenic right ventricular dysplasia 9 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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