rs1410924735

chr12-32796308-G-Achr12-32796308-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001005242.3(PKP2):c.2168-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,271,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000056 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKP2 NM_001005242.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001853
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.229

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-32796308-G-A is Benign according to our data. Variant chr12-32796308-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 464424.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000126 (160/1271954) while in subpopulation AMR AF= 0.000919 (34/36992). AF 95% confidence interval is 0.000676. There are 0 homozygotes in gnomad4_exome. There are 79 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.2168-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.2168-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 8 AN: 143384 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.0000257

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: 0.000453

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000458

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 160 AN: 1271954 Hom.: 0 Cov.: 29 AF XY: 0.000125 AC XY: 79 AN XY: 633982

Gnomad4 AFR exome AF: 0.000898

Gnomad4 AMR exome AF: 0.000919

Gnomad4 ASJ exome AF: 0.000224

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000120

Gnomad4 FIN exome AF: 0.0000210

Gnomad4 NFE exome AF: 0.0000741

Gnomad4 OTH exome AF: 0.000270

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000558 AC: 8 AN: 143384 Hom.: 0 Cov.: 31 AF XY: 0.0000144 AC XY: 1 AN XY: 69528

Gnomad4 AFR AF: 0.0000257

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000453

Gnomad4 NFE AF: 0.0000458

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000874 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 29, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	7.5
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0080
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: rs1410924735; hg19: chr12-32949242; COSMIC: COSV50732586; COSMIC: COSV50732586;