rs143004808

Variant names:

• chr12-32896656-C-T
• rs143004808
• NM_001005242.3:c.76G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-32896656-C-T
• chr12-32896656-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005242.3(PKP2):​c.76G>A​(p.Asp26Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0092 in 1,563,166 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D26E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0094 (98 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 1.68
• Publications: 28 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

ENSG00000309487 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076743364).
• BP6: Variant 12-32896656-C-T is Benign according to our data. Variant chr12-32896656-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00705 (1074/152332) while in subpopulation NFE AF = 0.00912 (620/68018). AF 95% confidence interval is 0.00852. There are 12 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1074 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.76G>A	p.Asp26Asn	missense	Exon 1 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.76G>A	p.Asp26Asn	missense	Exon 1 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.76G>A	p.Asp26Asn	missense	Exon 1 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.76G>A	p.Asp26Asn	missense	Exon 1 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.76G>A	p.Asp26Asn	missense	Exon 1 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.76G>A	p.Asp26Asn	missense	Exon 1 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1076 AN: 152214 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00846 AC: 1427 AN: 168710 AF XY: 0.00846

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00588

Gnomad ASJ exome AF: 0.0452

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00252

Gnomad NFE exome AF: 0.00974

Gnomad OTH exome AF: 0.00956

GnomAD4 exome AF: 0.00944 AC: 13313 AN: 1410834 Hom.: 98 Cov.: 32 AF XY: 0.00933 AC XY: 6525 AN XY: 699498

African (AFR) AF: 0.00162 AC: 52 AN: 32048

American (AMR) AF: 0.00549 AC: 220 AN: 40078

Ashkenazi Jewish (ASJ) AF: 0.0460 AC: 1167 AN: 25362

East Asian (EAS) AF: 0.0000534 AC: 2 AN: 37474

South Asian (SAS) AF: 0.00395 AC: 321 AN: 81290

European-Finnish (FIN) AF: 0.00306 AC: 110 AN: 35930

Middle Eastern (MID) AF: 0.0165 AC: 68 AN: 4128

European-Non Finnish (NFE) AF: 0.00969 AC: 10617 AN: 1095730

Other (OTH) AF: 0.0129 AC: 756 AN: 58794

GnomAD4 genome AF: 0.00705 AC: 1074 AN: 152332 Hom.: 12 Cov.: 33 AF XY: 0.00652 AC XY: 486 AN XY: 74490

African (AFR) AF: 0.00190 AC: 79 AN: 41592

American (AMR) AF: 0.00823 AC: 126 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 173 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4832

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10628

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00912 AC: 620 AN: 68018

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00659 Hom.: 15

Bravo AF: 0.00752

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.000965 AC: 4

ESP6500EA AF: 0.00683 AC: 56

ExAC AF: 0.00592 AC: 696

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	7	Arrhythmogenic right ventricular dysplasia 9 (7)
-	-	4	not provided (4)
-	-	2	Arrhythmogenic right ventricular cardiomyopathy (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0077	T
MetaSVM	Uncertain	0.033	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.30
MVP		0.90
MPC		0.63
ClinPred		0.019	T
GERP RS		4.1
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.30
gMVP		0.52
Mutation Taster		=96/4	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: rs143004808; hg19: chr12-33049590; COSMIC: COSV106083957; COSMIC: COSV106083957;