rs373222905

chr12-32878332-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

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. 14/20 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: -0.324

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 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 GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.548G>A	p.Ser183Asn	missense_variant	3/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.548G>A	p.Ser183Asn	missense_variant	3/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152158 Hom.: 0 Cov.: 32

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: 21 AN: 250586 Hom.: 0 AF XY: 0.0000886 AC XY: 12 AN XY: 135446

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: 74 AN: 1460756 Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34 AN XY: 726684

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: 5 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74332

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.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 16, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2022	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

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2022	Has been reported in association with Brugada syndrome and arrhythmogenic cardiomyopathy (ACM) (Cerrone et al., 2016; Hasdemir et al., 2015; Persampieri et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies showed that p.(S183N) was unable to rescue the decrease in sodium channel current caused by PKP2 knockdown (Cerrone et al.,2014); This variant is associated with the following publications: (PMID: 27085656, 25395996, 25998140, 34426522, 35052786, 31402444, 24352520, 32443836, 30662450, 30821013) -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 05, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

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	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	6.8
Dann	Benign	0.86
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.030	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
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	T
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

Other links and lift over

dbSNP: rs373222905; hg19: chr12-33031266;