rs121434421

Variant names:

• chr12-32802499-G-A
• rs121434421
• NM_001005242.3:c.2071C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-32802499-G-A
• chr12-32802499-G-C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS2_Supporting

The NM_001005242.3(PKP2):​c.2071C>T​(p.Arg691*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,461,446 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: "SCV000205873: Transgenic mice expressing p.Arg735X mutant protein in cardiac tissue resulted in exercise-dependent ARVC phenotype (Cruz 2015)." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PKP2 NM_001005242.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.15
• Publications: 28 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 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000205873: Transgenic mice expressing p.Arg735X mutant protein in cardiac tissue resulted in exercise-dependent ARVC phenotype (Cruz 2015).; SCV004839393: Functional studies on transgenic mice showed that cardiac overexpression of human p.Arg735* in mice induced exercise dependent ARVC phenotype, and thus the pathogenic mechanism of this variant was concluded as dominant negative (PMID: 25857910).; SCV001779650: Functional studies show that over-expression of human p.(R735*) in mice induced an exercise-dependent ARVC phenotype (Cruz et al., 2015);; SCV002727510: Transgenic mice with cardiac-specific expression of this variant developed exercise-dependent right ventricular dysfunction resembling ARVC (Cruz FM et al. J. Am. Coll. Cardiol., 2015 Apr;65:1438-50).; SCV005336430: Functional studies using transgenic mice demonstrated exercise-induced ARVC (Cruz et al. 2015. PubMed ID: 25857910).; SCV006064650: A functional study has shown that mice with heart-specific expression of the variant allele exhibit right ventricular systolic dysfunction (PMID: 37833253). In cardiac cells isolated from these mice, the mutant protein showed unstable conformation and abnormal subcellular localization and is associated with disorganized actin cytoskeleton and sarcomeric misalignment (PMID: 37833253).
• PP5: Variant 12-32802499-G-A is Pathogenic according to our data. Variant chr12-32802499-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 6 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_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.2071C>T	p.Arg691*	stop_gained	Exon 10 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.2203C>T	p.Arg735*	stop_gained	Exon 11 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.2071C>T	p.Arg691*	stop_gained	Exon 10 of 12	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.2071C>T	p.Arg691*	stop_gained	Exon 10 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.2203C>T	p.Arg735*	stop_gained	Exon 11 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.2071C>T	p.Arg691*	stop_gained	Exon 10 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251356 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461446 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111614

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000502 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Arrhythmogenic right ventricular cardiomyopathy (3)
3	-	-	Arrhythmogenic right ventricular dysplasia 9 (3)
2	-	-	not provided (2)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	PKP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		5.2
Vest4		0.88
GERP RS		2.7
Mutation Taster		=0/200	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: rs121434421; hg19: chr12-32955433;