Genetic Variant PKP3:c.233-62G>A (chr11-396546-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.233-62G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,171,976 control chromosomes in the GnomAD database, including 35,700 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 0.29 ( 8350 hom., cov: 34)

Exomes 𝑓: 0.20 ( 27350 hom. )

Consequence

PKP3
NM_007183.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.99

Publications

14 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=-0.87).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP3	NM_007183.4 link	c.233-62G>A		intron_variant	Intron 1 of 12	ENST00000331563.7	NP_009114.1	Q9Y446-1
PKP3	NM_001303029.2 link	c.278-62G>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.233-62G>A		intron_variant	Intron 1 of 12	1	NM_007183.4	ENSP00000331678.2		Q9Y446-1

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43463

AN:

151964

Hom.:

8328

Cov.:

show subpopulations

Gnomad AFR

AF:

0.522

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.558

Gnomad SAS

AF:

0.363

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.270

GnomAD4 exome

AF:

0.203

AC:

207092

AN:

1019894

Hom.:

27350

Cov.:

AF XY:

0.206

AC XY:

105538

AN XY:

512870

show subpopulations

African (AFR)

AF:

0.538

AC:

13034

AN:

24208

American (AMR)

AF:

0.250

AC:

8333

AN:

33358

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

3503

AN:

18702

East Asian (EAS)

AF:

0.602

AC:

21573

AN:

35840

South Asian (SAS)

AF:

0.342

AC:

22431

AN:

65636

European-Finnish (FIN)

AF:

0.130

AC:

6354

AN:

48706

Middle Eastern (MID)

AF:

0.240

AC:

754

AN:

3140

European-Non Finnish (NFE)

AF:

0.162

AC:

120760

AN:

745612

Other (OTH)

AF:

0.232

AC:

10350

AN:

44692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

7912

15824

23736

31648

39560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4254

8508

12762

17016

21270

<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:

0.286

AC:

43528

AN:

152082

Hom.:

8350

Cov.:

AF XY:

0.286

AC XY:

21300

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.522

AC:

21652

AN:

41448

American (AMR)

AF:

0.258

AC:

3935

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

623

AN:

3472

East Asian (EAS)

AF:

0.557

AC:

2867

AN:

5148

South Asian (SAS)

AF:

0.361

AC:

1740

AN:

4826

European-Finnish (FIN)

AF:

0.123

AC:

1302

AN:

10600

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.157

AC:

10676

AN:

67988

Other (OTH)

AF:

0.268

AC:

566

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1408

2817

4225

5634

7042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

424

848

1272

1696

2120

<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:

0.289

Hom.:

3507

Bravo

AF:

0.306

Asia WGS

AF:

0.456

AC:

1587

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.50

(source)

DANN

Benign

0.63

PhyloP100

-3.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over