Genetic Variant PKP3:c.233-300G>A (chr11-396308-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007183.4(PKP3):c.233-300G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 379,624 control chromosomes in the GnomAD database, including 12,435 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 5279 hom., cov: 33)

Exomes 𝑓: 0.21 ( 7156 hom. )

Consequence

PKP3
NM_007183.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.47

Publications

16 publications found

Variant links:

Genes affected

PKP3 (HGNC:9025): (plakophilin 3) 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 protein may act in cellular desmosome-dependent adhesion and signaling pathways. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

PKP3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP3	NM_007183.4 link	c.233-300G>A		intron_variant	Intron 1 of 12	ENST00000331563.7	NP_009114.1	Q9Y446-1
PKP3	NM_001303029.2 link	c.278-300G>A		intron_variant	Intron 2 of 13		NP_001289958.1	Q9Y446-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP3	ENST00000331563.7 link	c.233-300G>A		intron_variant	Intron 1 of 12	1	NM_007183.4	ENSP00000331678.2		Q9Y446-1

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36340

AN:

151990

Hom.:

5267

Cov.:

show subpopulations

Gnomad AFR

AF:

0.357

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.239

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.559

Gnomad SAS

AF:

0.362

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.231

GnomAD4 exome

AF:

0.208

AC:

47353

AN:

227516

Hom.:

7156

Cov.:

AF XY:

0.209

AC XY:

24168

AN XY:

115802

show subpopulations

African (AFR)

AF:

0.350

AC:

2217

AN:

6334

American (AMR)

AF:

0.226

AC:

1686

AN:

7464

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

1473

AN:

8172

East Asian (EAS)

AF:

0.619

AC:

10781

AN:

17426

South Asian (SAS)

AF:

0.304

AC:

3520

AN:

11588

European-Finnish (FIN)

AF:

0.129

AC:

2272

AN:

17570

Middle Eastern (MID)

AF:

0.230

AC:

269

AN:

1170

European-Non Finnish (NFE)

AF:

0.153

AC:

21931

AN:

142930

Other (OTH)

AF:

0.216

AC:

3204

AN:

14862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1553

3106

4659

6212

7765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.239

AC:

36388

AN:

152108

Hom.:

5279

Cov.:

AF XY:

0.240

AC XY:

17856

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.358

AC:

14821

AN:

41454

American (AMR)

AF:

0.240

AC:

3667

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

619

AN:

3470

East Asian (EAS)

AF:

0.558

AC:

2875

AN:

5150

South Asian (SAS)

AF:

0.359

AC:

1730

AN:

4820

European-Finnish (FIN)

AF:

0.123

AC:

1305

AN:

10620

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.158

AC:

10717

AN:

67978

Other (OTH)

AF:

0.229

AC:

484

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1339

2677

4016

5354

6693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.190

Hom.:

10632

Bravo

AF:

0.252

Asia WGS

AF:

0.441

AC:

1535

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.4

(source)

DANN

Benign

0.82

PhyloP100

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over