rs1454933

chr12-32864109-A-Cchr12-32864109-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001005242.3(PKP2):c.1170+4818T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,102 control chromosomes in the GnomAD database, including 1,678 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1678 hom., cov: 32)
• Consequence: PKP2 NM_001005242.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.466

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 (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.1170+4818T>G		intron_variant		ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1170+4818T>G		intron_variant		1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20953 AN: 151988 Hom.: 1675 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.147

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.138 AC: 20975 AN: 152102 Hom.: 1678 Cov.: 32 AF XY: 0.137 AC XY: 10185 AN XY: 74356

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.0563

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.145

Alfa AF: 0.128 Hom.: 372

Bravo AF: 0.148

Asia WGS AF: 0.182 AC: 636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	7.0
Dann	Benign	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

Other links and lift over

dbSNP: rs1454933; hg19: chr12-33017043;