rs10772008

Variant names:

• chr12-32821311-C-T
• rs10772008
• NM_001005242.3:c.2013+45G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005242.3(PKP2):​c.2013+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 1,517,982 control chromosomes in the GnomAD database, including 460,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41590 hom., cov: 32)
  • Exomes 𝑓: 0.78 (418743 hom.)
• Consequence: PKP2 NM_001005242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.697
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-32821311-C-T is Benign according to our data. Variant chr12-32821311-C-T is described in ClinVar as Benign. ClinVar VariationId is 259441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.2013+45G>A		intron_variant	Intron 9 of 12	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.2013+45G>A		intron_variant	Intron 9 of 12	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.731 AC: 111059 AN: 151952 Hom.: 41566 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.692

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.815

Gnomad MID AF: 0.742

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.732

GnomAD2 exomes AF: 0.703 AC: 175020 AN: 248858 AF XY: 0.711

Gnomad AFR exome AF: 0.656

Gnomad AMR exome AF: 0.526

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.350

Gnomad FIN exome AF: 0.814

Gnomad NFE exome AF: 0.817

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.775 AC: 1058965 AN: 1365912 Hom.: 418743 Cov.: 20 AF XY: 0.772 AC XY: 529563 AN XY: 685698

African (AFR) AF: 0.653 AC: 20615 AN: 31572

American (AMR) AF: 0.540 AC: 23989 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 20070 AN: 25554

East Asian (EAS) AF: 0.338 AC: 13246 AN: 39132

South Asian (SAS) AF: 0.608 AC: 51169 AN: 84158

European-Finnish (FIN) AF: 0.812 AC: 43242 AN: 53224

Middle Eastern (MID) AF: 0.766 AC: 4049 AN: 5288

European-Non Finnish (NFE) AF: 0.818 AC: 839182 AN: 1025448

Other (OTH) AF: 0.760 AC: 43403 AN: 57104

GnomAD4 genome AF: 0.731 AC: 111126 AN: 152070 Hom.: 41590 Cov.: 32 AF XY: 0.724 AC XY: 53800 AN XY: 74342

African (AFR) AF: 0.664 AC: 27535 AN: 41450

American (AMR) AF: 0.624 AC: 9532 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 2714 AN: 3472

East Asian (EAS) AF: 0.340 AC: 1757 AN: 5166

South Asian (SAS) AF: 0.596 AC: 2871 AN: 4816

European-Finnish (FIN) AF: 0.815 AC: 8618 AN: 10568

Middle Eastern (MID) AF: 0.736 AC: 215 AN: 292

European-Non Finnish (NFE) AF: 0.819 AC: 55719 AN: 68012

Other (OTH) AF: 0.726 AC: 1534 AN: 2114

Alfa AF: 0.780 Hom.: 129230

Bravo AF: 0.714

Asia WGS AF: 0.473 AC: 1647 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 9 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.78
PhyloP100		-0.70
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: rs10772008; hg19: chr12-32974245;