12-32796302-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001005242.3(PKP2):​c.2168-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000708 in 141,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PKP2
NM_001005242.3 splice_region, intron

Scores

2
Splicing: ADA: 0.00009608
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.47

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKP2NM_001005242.3 linkc.2168-4G>A splice_region_variant, intron_variant Intron 10 of 12 ENST00000340811.9 NP_001005242.2 Q99959-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKP2ENST00000340811.9 linkc.2168-4G>A splice_region_variant, intron_variant Intron 10 of 12 1 NM_001005242.3 ENSP00000342800.5 Q99959-2

Frequencies

GnomAD3 genomes
AF:
0.00000708
AC:
1
AN:
141154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000270
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000438
AC:
1
AN:
228390
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.0000675
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1383338
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
691060
African (AFR)
AF:
0.00
AC:
0
AN:
30042
American (AMR)
AF:
0.00
AC:
0
AN:
40680
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25088
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37322
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80696
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52832
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5544
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1053940
Other (OTH)
AF:
0.00
AC:
0
AN:
57194
GnomAD4 genome
AF:
0.00000708
AC:
1
AN:
141154
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
68158
show subpopulations
African (AFR)
AF:
0.0000270
AC:
1
AN:
37074
American (AMR)
AF:
0.00
AC:
0
AN:
14394
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3374
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3900
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4114
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9052
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
66076
Other (OTH)
AF:
0.00
AC:
0
AN:
1960
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
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

Genome 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
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.67
CADD
Benign
2.0
DANN
Benign
0.65
PhyloP100
-2.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000096
dbscSNV1_RF
Benign
0.0040
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs376231586; hg19: chr12-32949236; API