dbSNP rs10772008: PKP2:c.2013+45G>A (chr12-32821311-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001407157.1(PKP2):c.2190G>A(p.Leu730Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 1,517,982 control chromosomes in the GnomAD database, including 460,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 41590 hom., cov: 32)

Exomes 𝑓: 0.78 ( 418743 hom. )

Consequence

PKP2
NM_001407157.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.697

Publications

10 publications found

Variant links:

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

PKP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 12-32821311-C-T is Benign according to our data. Variant chr12-32821311-C-T is described in ClinVar as Benign. ClinVar VariationId is 259441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.697 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407157.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKP2	NM_001005242.3	MANE Select	c.2013+45G>A		intron	N/A	NP_001005242.2	Q99959-2
PKP2	NM_001407157.1		c.2190G>A	p.Leu730Leu	synonymous	Exon 10 of 10	NP_001394086.1
PKP2	NM_001407161.1		c.2058G>A	p.Leu686Leu	synonymous	Exon 9 of 9	NP_001394090.1	A0AAQ5BGY2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKP2	ENST00000340811.9	TSL:1 MANE Select	c.2013+45G>A		intron	N/A	ENSP00000342800.5	Q99959-2
PKP2	ENST00000070846.11	TSL:1	c.2145+45G>A		intron	N/A	ENSP00000070846.6	Q99959-1
PKP2	ENST00000700564.2		c.2058G>A	p.Leu686Leu	synonymous	Exon 9 of 9	ENSP00000519095.1	A0AAQ5BGY2

Frequencies

GnomAD3 genomes

AF:

0.731

AC:

111059

AN:

151952

Hom.:

41566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.664

Gnomad AMI

AF:

0.692

Gnomad AMR

AF:

0.624

Gnomad ASJ

AF:

0.782

Gnomad EAS

AF:

0.340

Gnomad SAS

AF:

0.594

Gnomad FIN

AF:

0.815

Gnomad MID

AF:

0.742

Gnomad NFE

AF:

0.819

Gnomad OTH

AF:

0.732

GnomAD2 exomes

AF:

0.703

AC:

175020

AN:

248858

AF XY:

0.711

show subpopulations

Gnomad AFR exome

AF:

0.656

Gnomad AMR exome

AF:

0.526

Gnomad ASJ exome

AF:

0.780

Gnomad EAS exome

AF:

0.350

Gnomad FIN exome

AF:

0.814

Gnomad NFE exome

AF:

0.817

Gnomad OTH exome

AF:

0.750

GnomAD4 exome

AF:

0.775

AC:

1058965

AN:

1365912

Hom.:

418743

Cov.:

AF XY:

0.772

AC XY:

529563

AN XY:

685698

show subpopulations

African (AFR)

AF:

0.653

AC:

20615

AN:

31572

American (AMR)

AF:

0.540

AC:

23989

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.785

AC:

20070

AN:

25554

East Asian (EAS)

AF:

0.338

AC:

13246

AN:

39132

South Asian (SAS)

AF:

0.608

AC:

51169

AN:

84158

European-Finnish (FIN)

AF:

0.812

AC:

43242

AN:

53224

Middle Eastern (MID)

AF:

0.766

AC:

4049

AN:

5288

European-Non Finnish (NFE)

AF:

0.818

AC:

839182

AN:

1025448

Other (OTH)

AF:

0.760

AC:

43403

AN:

57104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

11364

22727

34091

45454

56818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18454

36908

55362

73816

92270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.731

AC:

111126

AN:

152070

Hom.:

41590

Cov.:

AF XY:

0.724

AC XY:

53800

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.664

AC:

27535

AN:

41450

American (AMR)

AF:

0.624

AC:

9532

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.782

AC:

2714

AN:

3472

East Asian (EAS)

AF:

0.340

AC:

1757

AN:

5166

South Asian (SAS)

AF:

0.596

AC:

2871

AN:

4816

European-Finnish (FIN)

AF:

0.815

AC:

8618

AN:

10568

Middle Eastern (MID)

AF:

0.736

AC:

215

AN:

292

European-Non Finnish (NFE)

AF:

0.819

AC:

55719

AN:

68012

Other (OTH)

AF:

0.726

AC:

1534

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1460

2920

4381

5841

7301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

838

1676

2514

3352

4190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.780

Hom.:

129230

Bravo

AF:

0.714

Asia WGS

AF:

0.473

AC:

1647

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arrhythmogenic right ventricular dysplasia 9 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.3

(source)

DANN

Benign

0.78

PhyloP100

-0.70

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over