rs121434420

Variant names:

• chr12-32879021-G-A
• rs121434420
• NM_001005242.3:c.235C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-32879021-G-A
• chr12-32879021-G-C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PP3_Strong PP5_Very_Strong BS2_Supporting

The NM_001407158.1(PKP2):​c.-93C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000139 in 1,577,370 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000840033: "In addition, experimental studies have shown that this variant results in reduced PKP2 protein expression, a loss of localization to sites of cell-cell contact and reduces interaction with connexin 43 protein in vitro." PMID 19084810" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PKP2 NM_001407158.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 5.82
• Publications: 30 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000840033: "In addition, experimental studies have shown that this variant results in reduced PKP2 protein expression, a loss of localization to sites of cell-cell contact and reduces interaction with connexin 43 protein in vitro." PMID 19084810; SCV000236200: Published functional studies demonstrate that this variant reduces the expression level of plakophilin and alters desmosomal protein-protein interactions (Joshi-Mukherjee et al., 2008; Rasmussen et al., 2014);; SCV000280413: Joshi-Mukherjee et al (2008) studied the variant in neonatal rat ventricular myocytes in culture. They found that a truncated protein was expressed, which failed to localize appropriately and reduced expression of connexin-43 and loss of expression of HSP90. PMID:18948582; SCV000061874: "In vitro functional studies support that this variant results in reduced PKP2 expression (Joshi-Mukherjee 2008)."; SCV000318240: Functional in vitro analysis demonstrated poor localization to the cell membrane and altered desmosomal protein interactions with reduced expression (Joshi-Mukherjee, 2008).; SCV001357621: Experimental studies have shown that the PKP2 protein expression was decreased by 50% in cells from a heterozygous carrier compared with wild type (PMID: 24704780). It has been shown that the mutant protein does not localize to sites of cell-cell contact and shows reduced ability to interact with connexin 43 protein (PMID: 19084810).; SCV004046187: Functional studies showed this variant leads to reduced PKP2 expression, poor localization to the cell membrane and altered desmosomal protein interactions (PMID: 19084810, 24704780).; SCV000918024: This report showed the mutant protein failed to preferentially localize to sites of cell-cell apposition, resulted in reduced abundance of Cx43 after R79x expression and prevented its physical interaction with both DP and Cx43 (Joshi-Mukherjee_2008).
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.625
• PP5: Variant 12-32879021-G-A is Pathogenic according to our data. Variant chr12-32879021-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407158.1. 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.235C>T	p.Arg79*	stop_gained	Exon 2 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_001407158.1		c.-93C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	NP_001394087.1
	PKP2	NM_001407159.1		c.-93C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	NP_001394088.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.235C>T	p.Arg79*	stop_gained	Exon 2 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.235C>T	p.Arg79*	stop_gained	Exon 2 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.235C>T	p.Arg79*	stop_gained	Exon 2 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 32

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251328 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 15 AN: 1425290 Hom.: 0 Cov.: 26 AF XY: 0.0000112 AC XY: 8 AN XY: 711384

African (AFR) AF: 0.00 AC: 0 AN: 32700

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1080366

Other (OTH) AF: 0.00 AC: 0 AN: 59066

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000313 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Arrhythmogenic right ventricular dysplasia 9 (11)
8	-	-	not provided (8)
2	-	-	Cardiomyopathy (2)
1	-	-	Arrhythmogenic right ventricular cardiomyopathy (1)
1	-	-	Cardiac arrhythmia (1)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		5.8
Vest4		0.70
GERP RS		5.7
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs121434420; hg19: chr12-33031955; COSMIC: COSV50729880;