rs150821281

chr12-32878461-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001005242.3(PKP2):c.419C>T(p.Ser140Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,614,122 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S140T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (11 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:18
• Conservation: PhyloP100: 1.23

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045339167).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00242 (368/152264) while in subpopulation NFE AF= 0.00384 (261/68016). AF 95% confidence interval is 0.00345. There are 1 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 368 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.419C>T	p.Ser140Phe	missense_variant	3/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.419C>T	p.Ser140Phe	missense_variant	3/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 368 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00233 AC: 586 AN: 251402 Hom.: 1 AF XY: 0.00233 AC XY: 317 AN XY: 135876

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00361 AC: 5282 AN: 1461858 Hom.: 11 Cov.: 33 AF XY: 0.00347 AC XY: 2522 AN XY: 727230

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00148

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00430

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00242 AC: 368 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74450

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00384

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00290 Hom.: 0

Bravo AF: 0.00211

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00231 AC: 280

EpiCase AF: 0.00425

EpiControl AF: 0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:2 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 12, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Mar 09, 2016	- -

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2015	p.Ser140Phe in exon 3 of PKP2: This variant is not expected to have clinical sig nificance because it has been identified in 0.3% (219/66346) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs150821281). -
Likely benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 03, 2017	- -

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 26681313, 26264440, 15489853, 19095136, 20400443, 19955750, 21859740, 24055113, 23299917, 21606390, 20716751, 20857253, 19358943, 20031617, 17556197, 16549640, 16415378, 20152563, 18508782, 25016126, 26332594, 19569224, 25910212, 25569433, 27153395, 23270881, 26383259, 31402444) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PKP2: BP4, BS1, BS2 -

Cardiomyopathy Benign:4

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 20, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jun 26, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2018	- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Allele frequency may indicate a low penetrance or likely benign variant -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	14
Dann	Uncertain	0.98
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.055	T;D
Sift4G	Benign	0.094	T;T
Polyphen		0.0070	B;B
Vest4		0.18
MVP		0.62
MPC		0.17
ClinPred		0.011	T
GERP RS		2.4
Varity_R		0.070
gMVP		0.37

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: rs150821281; hg19: chr12-33031395;