rs144601090

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_ModeratePP5BS2

The NM_001005242.3(PKP2):c.1930T>C(p.Ser644Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:12

Conservation

PhyloP100: 7.97

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 -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

PP5

Variant 12-32821439-A-G is Pathogenic according to our data. Variant chr12-32821439-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45055.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=10}. Variant chr12-32821439-A-G is described in Lovd as [Pathogenic].

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3 link	c.1930T>C	p.Ser644Pro	missense_variant	Exon 9 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.1930T>C	p.Ser644Pro	missense_variant	Exon 9 of 13	1	NM_001005242.3	ENSP00000342800.5		Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251382

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000112

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1Uncertain:4

Nov 24, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser688Pro variant in PKP2 has been reported in 5 individuals with ARVC (van Tintelen 2006 PMID: 16567567, Quarta 2011 PMID: 21606390, and Zhang 2012 PMID: 22019812, Walsh 2017 PMID: 27532257, DeWitt 2019 PMID: 31319917, van Lint 2019 PMID: 31386562), in 1 individual with sudden unexplained death in the young (SUDY) (Shanks 2018 PMID: 29915097) and identified by our laboratory in 1 individual with DCM and ARVC and 2 individuals with ARVC. It has also been identified in 0.044% (11/24964) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PP3. -

Aug 06, 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 proline at codon 688 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 20031616, 21606390, 21606396, 22019812, 25820315, 27532257, 31319917, 32522011, 36720007, 37418234). This variant has also been reported in an individual affected with acute myocarditis (PMID: 28359509) and in a young individual with sudden unexplained death (PMID: 29915097). This variant has also been identified in 11/282770 chromosomes (11/24964 African 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. -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Arrhythmogenic right ventricular dysplasia 9

Pathogenic:1Uncertain:3

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 688 of the PKP2 protein (p.Ser688Pro). This variant is present in population databases (rs144601090, gnomAD 0.05%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 21606390, 22019812, 27532257, 31319917, 32522011; internal data). ClinVar contains an entry for this variant (Variation ID: 45055). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:3

Jan 28, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a child with acute myocarditis who was compound heterozygous for a paternally inherited S688P variant and a maternally inherited D829N variant; all family members were reported as unaffected (PMID: 28359509); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21606396, 31386562, 24033266, 22019812, 21606390, 16567567, 27532257, 20031616, 25637381, 23299917, 29915097, 23871674, 31402444, 36175056, 32522011, 33232181, 35819174, 28359509, 21636032) -

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 30, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3 -

Cardiomyopathy

Uncertain:2

Sep 13, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2023

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 proline at codon 688 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 20031616, 21606390, 21606396, 22019812, 25820315, 27532257, 31319917, 32522011). This variant has also been reported in an individual affected with acute myocarditis (PMID: 28359509) and in a young individual with sudden unexplained death (PMID: 29915097). This variant has also been identified in 11/282770 chromosomes (11/24964 African 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

Pathogenic:1

Mar 27, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S688P variant (also known as c.2062T>C), located in coding exon 10 of the PKP2 gene, results from a T to C substitution at nucleotide position 2062. The serine at codon 688 is replaced by proline, an amino acid with similar properties. This variant has been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Quarta G et al. Circulation, 2011 Jun;123:2701-9; Zhang M et al. Circ. J., 2012 Oct;76:189-94; DeWitt ES et al. J Am Coll Cardiol, 2019 07;74:346-358; Goudal A et al. Hum Mutat, 2022 Sep;43:1333-1342; Olivetti NQS et al. Circ Arrhythm Electrophysiol, 2023 Feb;16:e011391). This variant has also been seen in sudden death and exome cohorts, but cardiovascular details were limited or not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Shanks GW et al. Circulation, 2018 06;137:2705-2715). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;T

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.1

.;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.94

MVP

0.93

MPC

0.75

ClinPred

0.94

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.82

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