rs11476598

Variant names:

• chr12-32791224-CA-C
• rs11476598
• NM_001005242.3:c.*1199delT

Your query was ambiguous. Multiple possible variants found:

• chr12-32791224-CA-C
• chr12-32791224-CA-CAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001005242.3(PKP2):​c.*1199delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.61 (28623 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: PKP2 NM_001005242.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.175
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 12-32791224-CA-C is Benign according to our data. Variant chr12-32791224-CA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 308474.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.672 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.*1199delT		3_prime_UTR	Exon 13 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.*1199delT		3_prime_UTR	Exon 14 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.*1054delT		3_prime_UTR	Exon 12 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.*1199delT		3_prime_UTR	Exon 13 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.*1199delT		3_prime_UTR	Exon 14 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.*1054delT		3_prime_UTR	Exon 12 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91626 AN: 151376 Hom.: 28606 Cov.: 0

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.602

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.605 AC: 91690 AN: 151494 Hom.: 28623 Cov.: 0 AF XY: 0.598 AC XY: 44240 AN XY: 74014

African (AFR) AF: 0.561 AC: 23159 AN: 41306

American (AMR) AF: 0.517 AC: 7882 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2169 AN: 3460

East Asian (EAS) AF: 0.212 AC: 1093 AN: 5148

South Asian (SAS) AF: 0.398 AC: 1915 AN: 4812

European-Finnish (FIN) AF: 0.728 AC: 7597 AN: 10442

Middle Eastern (MID) AF: 0.586 AC: 170 AN: 290

European-Non Finnish (NFE) AF: 0.677 AC: 45899 AN: 67766

Other (OTH) AF: 0.598 AC: 1264 AN: 2112

Alfa AF: 0.638 Hom.: 3853

Bravo AF: 0.592

Asia WGS AF: 0.305 AC: 1062 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.17
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: rs11476598; hg19: chr12-32944158; COSMIC: COSV50726797; COSMIC: COSV50726797;