rs397516985

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001005242.3(PKP2):c.1130T>C(p.Ile377Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,848 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I377V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.49

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3 linkuse as main transcript	c.1130T>C	p.Ile377Thr	missense_variant	4/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9 linkuse as main transcript	c.1130T>C	p.Ile377Thr	missense_variant	4/13	1	NM_001005242.3	P1	Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2017	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 45009). This variant is present in population databases (rs397516985, ExAC 0.01%). This sequence change replaces isoleucine with threonine at codon 377 of the PKP2 protein (p.Ile377Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 25, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Ile377Thr v ariant (PKP2) has not been reported in the literature nor previously identified by our laboratory. Computational analyses (biochemical amino acid properties, co nservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ile377Thr variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. This variant has not been identified in large and broad popu lations by the NHBLI Exome Sequencing Project (http://evs.gs.washington.edu/EVS) . Although computational predictions and absence in the general population suppo rt that the Ile377Thr variant may be pathogenic, additional studies are needed t o fully assess its clinical significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2021

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 45009; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2020

The c.1130T>C (p.I377T) alteration is located in exon 4 (coding exon 4) of the PKP2 gene. This alteration results from a T to C substitution at nucleotide position 1130, causing the isoleucine (I) at amino acid position 377 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.76

Gain of disorder (P = 0.0285);Gain of disorder (P = 0.0285);

MVP

0.84

MPC

0.71

ClinPred

1.0

GERP RS

5.0

Varity_R

0.74

gMVP

0.69

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