rs143900944

Variant names:

• chr12-32869004-T-C
• rs143900944
• NM_001005242.3:c.1093A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-32869004-T-C
• chr12-32869004-T-G

Variant summary

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

The NM_004572.4(PKP2):​c.1093A>G​(p.Met365Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,613,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. M365I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: PKP2 NM_004572.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9
• Conservation: PhyloP100: 1.15
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.034095913).
• BP6: Variant 12-32869004-T-C is Benign according to our data. Variant chr12-32869004-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164963.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000118 (18/152320) while in subpopulation SAS AF = 0.00166 (8/4820). AF 95% confidence interval is 0.000825. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 18 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004572.4. 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.1093A>G	p.Met365Val	missense	Exon 4 of 13	NP_001005242.2
	PKP2	NM_004572.4		c.1093A>G	p.Met365Val	missense	Exon 4 of 14	NP_004563.2
	PKP2	NM_001407155.1		c.1093A>G	p.Met365Val	missense	Exon 4 of 12	NP_001394084.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.1093A>G	p.Met365Val	missense	Exon 4 of 13	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.1093A>G	p.Met365Val	missense	Exon 4 of 14	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.1093A>G	p.Met365Val	missense	Exon 4 of 12	ENSP00000515065.2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152202 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: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000267 AC: 67 AN: 251320 AF XY: 0.000317

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000222 AC: 324 AN: 1461464 Hom.: 1 Cov.: 32 AF XY: 0.000242 AC XY: 176 AN XY: 727068

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00125 AC: 108 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5744

European-Non Finnish (NFE) AF: 0.000173 AC: 192 AN: 1111742

Other (OTH) AF: 0.000215 AC: 13 AN: 60374

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.3
DANN	Benign	0.36
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.63
Sift	Benign	0.48	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.20
MVP		0.55
MPC		0.16
ClinPred		0.013	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.32
Mutation Taster		=99/1	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: rs143900944; hg19: chr12-33021938;