rs10772008

chr12-32821311-C-T

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: -0.697

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 259441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32821311-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PKP2	NM_001005242.3	c.2013+45G>A		intron_variant		ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.2013+45G>A		intron_variant		1	NM_001005242.3	P1

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

GnomAD3 exomes AF: 0.703 AC: 175020 AN: 248858 Hom.: 64300 AF XY: 0.711 AC XY: 95728 AN XY: 134600

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 SAS exome AF: 0.608

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

Gnomad4 AFR exome AF: 0.653

Gnomad4 AMR exome AF: 0.540

Gnomad4 ASJ exome AF: 0.785

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.608

Gnomad4 FIN exome AF: 0.812

Gnomad4 NFE exome AF: 0.818

Gnomad4 OTH exome AF: 0.760

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

Gnomad4 AFR AF: 0.664

Gnomad4 AMR AF: 0.624

Gnomad4 ASJ AF: 0.782

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.596

Gnomad4 FIN AF: 0.815

Gnomad4 NFE AF: 0.819

Gnomad4 OTH AF: 0.726

Alfa AF: 0.793 Hom.: 82592

Bravo AF: 0.714

Asia WGS AF: 0.473 AC: 1647 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Arrhythmogenic right ventricular dysplasia 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	1.3
Dann	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs10772008; hg19: chr12-32974245;