rs373222905

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_001005242.3(PKP2):c.548G>A(p.Ser183Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,612,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: -0.324

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity PKP2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.029903442).

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3 link	c.548G>A	p.Ser183Asn	missense_variant	Exon 3 of 13	ENST00000340811.9	NP_001005242.2	Q99959-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9 link	c.548G>A	p.Ser183Asn	missense_variant	Exon 3 of 13	1	NM_001005242.3	ENSP00000342800.5		Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000838

AC:

AN:

250586

Hom.:

AF XY:

0.0000886

AC XY:

AN XY:

135446

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000507

AC:

AN:

1460756

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00122

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Uncertain:3

Jul 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 183 of the PKP2 protein (p.Ser183Asn). This variant is present in population databases (rs373222905, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Brugada syndrome and arrhythmogenic cardiomyopathy (PMID: 24352520, 25998140, 32443836). ClinVar contains an entry for this variant (Variation ID: 201974). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PKP2 function (PMID: 24352520). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:2

Dec 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified in HGMD as DM, related to Brugada syndrome and reported in one patient with spontaneous ECG pattern during febrile episode. An in vitro construct with this variant showed that the mutant cells could not rescue the knockdown of PKP2 and that this mutant leads to decreased sodium current. This variant is classified in ClinVar with 1 star as Pathogenic by GeneDx. The variant has a Max MAF of 0.015% in ExAC (1 allele) and 0.1% in gnomAD (10 Ashkenazi alleles). It is predicted to be benign by prediction tools. 3 mammals and 6 non-mammals have an Asn at this position. -

Sep 26, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKP2 c.548G>A (p.Ser183Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251118 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (8.4e-05 vs 0.00065), allowing no conclusion about variant significance. c.548G>A has been reported in the literature in individuals affected with Arrhythmogenic Cardiomyopathy or Brugada syndrome (Cerrone_2014, Le Scouarnec_2015, Hasdemir_2015, Persampieri_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. At least one functional study reports experimental evidence evaluating an impact on protein function and failed to rescue the INa deficit observed in PKP2-KD cells (Cerrone_2014). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance -

not provided

Uncertain:2

Mar 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with Brugada syndrome and arrhythmogenic cardiomyopathy (ACM) (PMID: 24352520, 25998140, 32443836, 29940860, 35712781); Functional studies showed that p.(S183N) was unable to rescue the decrease in sodium channel current caused by PKP2 knockdown (PMID: 24352520); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27085656, 25395996, 25998140, 34426522, 35052786, 31402444, 30662450, 30821013, 24352520, 32443836, 25650408, 29192238, 28471438, 29940860, 35712781) -

Cardiomyopathy

Uncertain:1

Jan 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with asparagine at codon 183 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that the mutant protein carrying this variant was unable to rescue the phenotype of the PKP2 knock-down cells, suggesting that this variant may have deleterious impact on the protein function (PMID: 24352520). This variant has been reported in an individual who showed spontaneous Brugada type I electrocardiogram during a febrile episode (PMID: 24352520), as well as in two individuals affected with arrhythmogenic cardiomyopathy (PMID: 32443836, 35712781). This variant has also been identified in 23/281966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with asparagine at codon 183 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A functional study has shown that the mutant protein carrying this variant was unable to rescue the phenotype of the PKP2 knock-down cells, suggesting that this variant may have deleterious impact on the protein function (PMID: 24352520). This variant has been reported in an individual who showed spontaneous Brugada type I electrocardiogram during a febrile episode (PMID: 24352520), as well as in two individuals affected with arrhythmogenic cardiomyopathy (PMID: 32443836, 35712781). This variant has also been identified in 23/281966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S183N variant (also known as c.548G>A), located in coding exon 3 of the PKP2 gene, results from a G to A substitution at nucleotide position 548. The serine at codon 183 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in Brugada syndrome cohorts, and in vitro studies suggested that this alteration might affect sodium current; however, the physiological correlation is unclear (Cerrone M et al. Circulation, 2014 Mar;129:1092-103; Campuzano O et al. Int J Cardiol, 2016 Jul;214:403-5). Additionally, this alteration has been reported in an individual with concerns for arrhythmogenic right ventricular cardiomyopathy (ARVC) (Persampieri S et al. Genes (Basel), 2020 05;11:). This alteration has also been noted in whole exome sequencing cohorts Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230; Kars ME et al. Proc Natl Acad Sci U S A, 2021 09;118:).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.8

DANN

Benign

0.86

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.2

L;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.64

N;N

REVEL

Pathogenic

0.68

Sift

Benign

0.56

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.0010

B;B

Vest4

0.11

MutPred

0.27

Loss of phosphorylation at S183 (P = 0.0467);Loss of phosphorylation at S183 (P = 0.0467);

MVP

0.75

MPC

0.14

ClinPred

0.018

GERP RS

3.0

Varity_R

0.031

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over