rs373380483

chr12-32878304-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001005242.3(PKP2):c.576G>A(p.Pro192=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,188 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PKP2 NM_001005242.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.50

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-32878304-C-T is Benign according to our data. Variant chr12-32878304-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 533051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.5 with no splicing effect.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.576G>A	p.Pro192=	synonymous_variant	3/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.576G>A	p.Pro192=	synonymous_variant	3/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 250830 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135582

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461042 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 726820

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74320

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000121

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 08, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.4
Dann	Benign	0.66

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: rs373380483; hg19: chr12-33031238; COSMIC: COSV50727674;