12-32877927-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005242.3(PKP2):c.953A>C(p.His318Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,614,144 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H318H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 1.19

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_001005242.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.015997201).
• BP6: Variant 12-32877927-T-G is Benign according to our data. Variant chr12-32877927-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 374967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000919 (14/152304) while in subpopulation EAS AF= 0.00271 (14/5174). AF 95% confidence interval is 0.00164. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.953A>C	p.His318Pro	missense_variant	3/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.953A>C	p.His318Pro	missense_variant	3/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00270

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: 0.0000917 AC: 23 AN: 250850 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000235 AC: 344 AN: 1461840 Hom.: 4 Cov.: 33 AF XY: 0.000241 AC XY: 175 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00861

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00271

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 26, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 17, 2023

Variant summary: PKP2 c.953A>C (p.His318Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 328294 control chromosomes, including 10 homozygotes (gnomAD and jMorp databases (Tadaka_2021)). The observed variant frequency is approximately 5.72 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065), strongly suggesting that the variant is benign. c.953A>C has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, however without strong evidence for causality (e.g., Ohno_2013, Wada_2017). These reports therefore do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. The following publications have been ascertained in the context of this evaluation (PMID: 33179747, 23514727, 29178656). Five ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: 4 submitters classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 18, 2020

- -

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

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2019

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
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	13
Dann	Benign	0.54
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.33	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.31	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0	B;B
Vest4		0.15
MVP		0.81
MPC		0.25
ClinPred		0.018	T
GERP RS		2.6
Varity_R		0.12
gMVP		0.42

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: rs181098323; hg19: chr12-33030861;