rs139139859

Variant names:

• chr12-32878375-T-C
• rs139139859
• NM_001005242.3:c.505A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001005242.3(PKP2):​c.505A>G​(p.Ser169Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,613,992 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S169N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:18
• Conservation: PhyloP100: -0.0400
• Publications: 14 publications found

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]

PKP2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000309501 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059331954).
• BP6: Variant 12-32878375-T-C is Benign according to our data. Variant chr12-32878375-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45081.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000959 (146/152240) while in subpopulation NFE AF = 0.00171 (116/68010). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 146 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005242.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	NM_001005242.3	MANE Select	c.505A>G	p.Ser169Gly	missense	Exon 3 of 13	NP_001005242.2
	PKP2	NM_004572.4		c.505A>G	p.Ser169Gly	missense	Exon 3 of 14	NP_004563.2
	PKP2	NM_001407155.1		c.505A>G	p.Ser169Gly	missense	Exon 3 of 12	NP_001394084.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.505A>G	p.Ser169Gly	missense	Exon 3 of 13	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.505A>G	p.Ser169Gly	missense	Exon 3 of 14	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.505A>G	p.Ser169Gly	missense	Exon 3 of 12	ENSP00000515065.2

Frequencies

GnomAD3 genomes AF: 0.000960 AC: 146 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00117 AC: 294 AN: 251282 AF XY: 0.00138

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00187 AC: 2735 AN: 1461752 Hom.: 9 Cov.: 33 AF XY: 0.00194 AC XY: 1413 AN XY: 727176

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00256 AC: 221 AN: 86254

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53324

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00211 AC: 2348 AN: 1111984

Other (OTH) AF: 0.00204 AC: 123 AN: 60392

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74428

African (AFR) AF: 0.000193 AC: 8 AN: 41550

American (AMR) AF: 0.000915 AC: 14 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000956

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00122 AC: 148

EpiCase AF: 0.00218

EpiControl AF: 0.00154

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Arrhythmogenic right ventricular dysplasia 9 (5)
-	-	5	not provided (5)
-	1	4	not specified (5)
-	2	-	Arrhythmogenic right ventricular cardiomyopathy (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	PKP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	6.9
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.60	N
PhyloP100		-0.040
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.52
Sift	Benign	0.30	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.54
MPC		0.14
ClinPred		0.0035	T
GERP RS		-1.5
Varity_R		0.032
gMVP		0.23
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139139859; hg19: chr12-33031309;