Genetic Variant PKP4:p.Ala22Ala (chr2-158533250-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_003628.6(PKP4):c.66C>T(p.Ala22Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.0571 in 1,613,912 control chromosomes in the GnomAD database, including 3,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A22A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.053 ( 288 hom., cov: 32)

Exomes 𝑓: 0.058 ( 2831 hom. )

Consequence

PKP4
NM_003628.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.60

Variant links:

Genes affected

PKP4 (HGNC:9026): (plakophilin 4) Armadillo-like proteins are characterized by a series of armadillo repeats, first defined in the Drosophila 'armadillo' gene product, that are typically 42 to 45 amino acids in length. These proteins can be divided into subfamilies based on their number of repeats, their overall sequence similarity, and the dispersion of the repeats throughout their sequences. Members of the p120(ctn)/plakophilin subfamily of Armadillo-like proteins, including CTNND1, CTNND2, PKP1, PKP2, PKP4, and ARVCF. PKP4 may be a component of desmosomal plaque and other adhesion plaques and is thought to be involved in regulating junctional plaque organization and cadherin function. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2015]

PKP4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 2-158533250-C-T is Benign according to our data. Variant chr2-158533250-C-T is described in ClinVar as [Benign]. Clinvar id is 1230040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP4	NM_003628.6 link	c.66C>T	p.Ala22Ala	synonymous_variant	Exon 2 of 22	ENST00000389759.8	NP_003619.2	Q99569-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP4	ENST00000389759.8 link	c.66C>T	p.Ala22Ala	synonymous_variant	Exon 2 of 22	1	NM_003628.6	ENSP00000374409.3		Q99569-1

Frequencies

GnomAD3 genomes

AF:

0.0526

AC:

8008

AN:

152104

Hom.:

289

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0186

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.0630

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0662

Gnomad OTH

AF:

0.0584

GnomAD3 exomes

AF:

0.0527

AC:

13227

AN:

251068

Hom.:

537

AF XY:

0.0521

AC XY:

7072

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.0185

Gnomad AMR exome

AF:

0.0415

Gnomad ASJ exome

AF:

0.0404

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0179

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.0662

Gnomad OTH exome

AF:

0.0666

GnomAD4 exome

AF:

0.0575

AC:

84119

AN:

1461690

Hom.:

2831

Cov.:

AF XY:

0.0571

AC XY:

41522

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0150

Gnomad4 AMR exome

AF:

0.0427

Gnomad4 ASJ exome

AF:

0.0396

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0188

Gnomad4 FIN exome

AF:

0.114

Gnomad4 NFE exome

AF:

0.0624

Gnomad4 OTH exome

AF:

0.0524

GnomAD4 genome

AF:

0.0526

AC:

8011

AN:

152222

Hom.:

288

Cov.:

AF XY:

0.0543

AC XY:

4041

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0186

Gnomad4 AMR

AF:

0.0630

Gnomad4 ASJ

AF:

0.0401

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0172

Gnomad4 FIN

AF:

0.122

Gnomad4 NFE

AF:

0.0662

Gnomad4 OTH

AF:

0.0578

Alfa

AF:

0.0591

Hom.:

139

Bravo

AF:

0.0454

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0662

EpiControl

AF:

0.0639

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over