rs1454933

Variant names:

• chr12-32864109-A-C
• rs1454933
• NM_001005242.3:c.1170+4818T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-32864109-A-C
• chr12-32864109-A-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005242.3. 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.1170+4818T>G		intron	N/A	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.1170+4818T>G		intron	N/A	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.1170+4818T>G		intron	N/A	NP_001394084.1	A0A8V8TPU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.1170+4818T>G		intron	N/A	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.1170+4818T>G		intron	N/A	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.1170+4818T>G		intron	N/A	ENSP00000515065.2	A0A8V8TPU9

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

African (AFR) AF: 0.190 AC: 7886 AN: 41438

American (AMR) AF: 0.148 AC: 2267 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3470

East Asian (EAS) AF: 0.151 AC: 784 AN: 5190

South Asian (SAS) AF: 0.194 AC: 934 AN: 4824

European-Finnish (FIN) AF: 0.0563 AC: 596 AN: 10584

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7720 AN: 68004

Other (OTH) AF: 0.145 AC: 306 AN: 2108

Alfa AF: 0.141 Hom.: 1442

Bravo AF: 0.148

Asia WGS AF: 0.182 AC: 636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.0
DANN	Benign	0.69
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1454933; hg19: chr12-33017043;