rs185681814

Positions:

• chr12-32878903-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000340811.9(PKP2):​c.336+17T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,271,822 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PKP2 ENST00000340811.9 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -1.58

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000176 (197/1119506) while in subpopulation MID AF= 0.00145 (5/3454). AF 95% confidence interval is 0.00057. There are 0 homozygotes in gnomad4_exome. There are 95 alleles in male gnomad4_exome subpopulation. Median coverage is 16. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.336+17T>G		intron_variant		ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.336+17T>G		intron_variant		1	NM_001005242.3	ENSP00000342800	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 251322 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000176 AC: 197 AN: 1119506 Hom.: 0 Cov.: 16 AF XY: 0.000166 AC XY: 95 AN XY: 573360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000452

Gnomad4 ASJ exome AF: 0.000208

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000655

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000257

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2018

A variant of uncertain significance has been identified in the PKP2 gene. The c.336+17 T>G variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant is observed in 6/11,536 alleles (0.05%) from individuals of Latino ancestry in large population cohorts (Lek et al., 2016). Other splice site variants in the PKP2 gene have been reported in the Human Gene Mutation Database in association with ARVD/C (Stenson et al., 2014). The c.336+17 T>G variant is predicted to create a strong downstream cryptic splice donor site in intron 2 and may cause abnormal gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.4
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs185681814; hg19: chr12-33031837;