12-32879035-G-C

Variant names:

• chr12-32879035-G-C
• rs786204387
• NM_001005242.3:c.224-3C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004572.4(PKP2):​c.224-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000236 in 1,273,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: PKP2 NM_004572.4 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.74
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004572.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	NM_001005242.3	MANE Select	c.224-3C>G		splice_region intron	N/A	NP_001005242.2
	PKP2	NM_004572.4		c.224-3C>G		splice_region intron	N/A	NP_004563.2
	PKP2	NM_001407155.1		c.224-3C>G		splice_region intron	N/A	NP_001394084.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.224-3C>G		splice_region intron	N/A	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.224-3C>G		splice_region intron	N/A	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.224-3C>G		splice_region intron	N/A	ENSP00000515065.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000236 AC: 3 AN: 1273286 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 643356

African (AFR) AF: 0.00 AC: 0 AN: 29658

American (AMR) AF: 0.00 AC: 0 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24942

East Asian (EAS) AF: 0.00 AC: 0 AN: 38836

South Asian (SAS) AF: 0.00 AC: 0 AN: 82322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3878

European-Non Finnish (NFE) AF: 0.00000318 AC: 3 AN: 942020

Other (OTH) AF: 0.00 AC: 0 AN: 53928

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Arrhythmogenic right ventricular dysplasia 9 (2)
-	1	-	Arrhythmogenic right ventricular cardiomyopathy (1)
-	1	-	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.84
PhyloP100		1.7
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.52		Position offset: -3

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

Other links and lift over

dbSNP: rs786204387; hg19: chr12-33031969;