rs147240502

Variant names:

• chr12-32841124-A-C
• rs147240502
• NM_001005242.3:c.1460T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-32841124-A-C
• chr12-32841124-A-T

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.1460T>G​(p.Ile487Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,612,890 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (28 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 7.83
• Publications: 21 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0121154785).
• BP6: Variant 12-32841124-A-C is Benign according to our data. Variant chr12-32841124-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45035.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 = 0.00397 (604/152244) while in subpopulation NFE AF = 0.00429 (292/68020). AF 95% confidence interval is 0.00389. There are 5 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 604 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.1460T>G	p.Ile487Ser	missense	Exon 6 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.1592T>G	p.Ile531Ser	missense	Exon 7 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.1460T>G	p.Ile487Ser	missense	Exon 6 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.1460T>G	p.Ile487Ser	missense	Exon 6 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.1592T>G	p.Ile531Ser	missense	Exon 7 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.1460T>G	p.Ile487Ser	missense	Exon 6 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 604 AN: 152126 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00480 AC: 1207 AN: 251382 AF XY: 0.00482

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0232

Gnomad NFE exome AF: 0.00533

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00411 AC: 6000 AN: 1460646 Hom.: 28 Cov.: 30 AF XY: 0.00406 AC XY: 2948 AN XY: 726754

African (AFR) AF: 0.000329 AC: 11 AN: 33450

American (AMR) AF: 0.00165 AC: 74 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26122

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.0214 AC: 1144 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00413 AC: 4590 AN: 1110904

Other (OTH) AF: 0.00272 AC: 164 AN: 60342

GnomAD4 genome AF: 0.00397 AC: 604 AN: 152244 Hom.: 5 Cov.: 32 AF XY: 0.00476 AC XY: 354 AN XY: 74432

African (AFR) AF: 0.000433 AC: 18 AN: 41546

American (AMR) AF: 0.00327 AC: 50 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0224 AC: 237 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00429 AC: 292 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00421 Hom.: 1

Bravo AF: 0.00233

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00472 AC: 573

EpiCase AF: 0.00387

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.8
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.88
MVP		0.84
MPC		0.51
ClinPred		0.045	T
GERP RS		5.2
Varity_R		0.76
gMVP		0.83
Mutation Taster		=92/8	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: rs147240502; hg19: chr12-32994058;