chr12-32878461-G-A

Variant names:

• chr12-32878461-G-A
• rs150821281
• NM_001005242.3:c.419C>T

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.419C>T​(p.Ser140Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,614,122 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts 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. S140T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (11 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:19
• Conservation: PhyloP100: 1.23
• Publications: 26 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: G2P, Labcorp Genetics (formerly Invitae)
• 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=0.0045339167).
• BP6: Variant 12-32878461-G-A is Benign according to our data. Variant chr12-32878461-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45077.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00242 (368/152264) while in subpopulation NFE AF = 0.00384 (261/68016). AF 95% confidence interval is 0.00345. There are 1 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 368 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	NM_001005242.3	MANE Select	c.419C>T	p.Ser140Phe	missense	Exon 3 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.419C>T	p.Ser140Phe	missense	Exon 3 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.419C>T	p.Ser140Phe	missense	Exon 3 of 12	NP_001394084.1	A0A8V8TPU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.419C>T	p.Ser140Phe	missense	Exon 3 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.419C>T	p.Ser140Phe	missense	Exon 3 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.419C>T	p.Ser140Phe	missense	Exon 3 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 368 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00233 AC: 586 AN: 251402 AF XY: 0.00233

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00361 AC: 5282 AN: 1461858 Hom.: 11 Cov.: 33 AF XY: 0.00347 AC XY: 2522 AN XY: 727230

African (AFR) AF: 0.000568 AC: 19 AN: 33476

American (AMR) AF: 0.00130 AC: 58 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00148 AC: 128 AN: 86254

European-Finnish (FIN) AF: 0.00139 AC: 74 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00430 AC: 4782 AN: 1111994

Other (OTH) AF: 0.00349 AC: 211 AN: 60394

GnomAD4 genome AF: 0.00242 AC: 368 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74450

African (AFR) AF: 0.000842 AC: 35 AN: 41564

American (AMR) AF: 0.00248 AC: 38 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00384 AC: 261 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00290 Hom.: 0

Bravo AF: 0.00211

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00231 AC: 280

EpiCase AF: 0.00425

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	Arrhythmogenic right ventricular dysplasia 9 (6)
-	-	5	not specified (5)
-	-	4	Cardiomyopathy (4)
-	1	3	not provided (4)
-	1	2	Arrhythmogenic right ventricular cardiomyopathy (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.2
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.47
Sift	Benign	0.055	T
Sift4G	Benign	0.094	T
Polyphen		0.0070	B
Vest4		0.18
MVP		0.62
MPC		0.17
ClinPred		0.011	T
GERP RS		2.4
Varity_R		0.070
gMVP		0.37
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs150821281; hg19: chr12-33031395;