ENST00000070846.11:c.1382A>G

Variant names:

• chr12-32843310-T-C
• rs376606525
• ENST00000070846.11:c.1382A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The ENST00000070846.11(PKP2):​c.1382A>G​(p.His461Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000825 in 1,212,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. H461Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: PKP2 ENST00000070846.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.02
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 19 uncertain in ENST00000070846.11
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05481094).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000070846.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	NM_001005242.3	MANE Select	c.1379-2105A>G		intron	N/A	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.1382A>G	p.His461Arg	missense	Exon 6 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407157.1		c.1382A>G	p.His461Arg	missense	Exon 6 of 10	NP_001394086.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000070846.11	TSL:1	c.1382A>G	p.His461Arg	missense	Exon 6 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.1379-2105A>G		intron	N/A	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000700559.2		c.1379-2105A>G		intron	N/A	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.25e-7 AC: 1 AN: 1212820 Hom.: 0 Cov.: 28 AF XY: 0.00000166 AC XY: 1 AN XY: 601212

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26278

American (AMR) AF: 0.00 AC: 0 AN: 37288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16892

East Asian (EAS) AF: 0.00 AC: 0 AN: 16796

South Asian (SAS) AF: 0.00 AC: 0 AN: 83204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4468

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 953204

Other (OTH) AF: 0.0000227 AC: 1 AN: 43990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Arrhythmogenic right ventricular dysplasia 9 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.52
DANN	Benign	0.19
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.20
Sift	Benign	0.55	T
Sift4G	Benign	0.95	T
Polyphen		0.0020	B
Vest4		0.062
MutPred		0.59		Gain of MoRF binding (P = 0.0134)
MVP		0.75
MPC		0.19
ClinPred		0.069	T
GERP RS		-1.2
Varity_R		0.050
gMVP		0.30
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs376606525; hg19: chr12-32996244;