GeneBe

rs1555143134

Variant names:

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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.08

Publications

0 publications found
Variant links:
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 cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • arrhythmogenic right ventricular dysplasia 9
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • left ventricular noncompaction
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Brugada syndrome
    Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
  • Brugada syndrome 1
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
  • catecholaminergic polymorphic ventricular tachycardia
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
  • dilated cardiomyopathy
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

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 id is 406551.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKP2NM_001005242.3 linkc.1593_1596dupGATG p.Arg533AspfsTer5 frameshift_variant Exon 7 of 13 ENST00000340811.9 NP_001005242.2 Q99959-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKP2ENST00000340811.9 linkc.1593_1596dupGATG p.Arg533AspfsTer5 frameshift_variant Exon 7 of 13 1 NM_001005242.3 ENSP00000342800.5 Q99959-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461258
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726978
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33470
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53184
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111652
Other (OTH)
AF:
0.00
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
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1
Jul 25, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 406551). This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 16799251, 22214898, 23514727). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg577Aspfs*5) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
5.1
Mutation Taster
=2/198
disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1555143134; hg19: chr12-32977056; API