Genetic Variant PKP4:c.-5-301C>T (chr2-158532879-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_003628.6(PKP4):c.-5-301C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 152,254 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.032 ( 166 hom., cov: 33)

Consequence

PKP4
NM_003628.6 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.747

Publications

0 publications found

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 was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-158532879-C-T is Benign according to our data. Variant chr2-158532879-C-T is described in ClinVar as Benign. ClinVar VariationId is 1290244.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003628.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PKP4	NM_003628.6	MANE Select	c.-5-301C>T	intron	N/A	NP_003619.2	Q99569-1
PKP4	NM_001377218.1		c.-5-301C>T	intron	N/A	NP_001364147.1	Q99569-1
PKP4	NM_001304969.3		c.-5-301C>T	intron	N/A	NP_001291898.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PKP4	ENST00000389759.8	TSL:1 MANE Select	c.-5-301C>T	intron	N/A	ENSP00000374409.3	Q99569-1
PKP4	ENST00000389757.7	TSL:1	c.-5-301C>T	intron	N/A	ENSP00000374407.3	Q99569-2
PKP4	ENST00000426248.7	TSL:1	n.-5-301C>T	intron	N/A	ENSP00000396827.2	E7EST6

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4818

AN:

152136

Hom.:

166

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0701

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.134

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.0234

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0317

AC:

4828

AN:

152254

Hom.:

166

Cov.:

AF XY:

0.0319

AC XY:

2373

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0701

AC:

2911

AN:

41540

American (AMR)

AF:

0.0122

AC:

187

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3468

East Asian (EAS)

AF:

0.134

AC:

694

AN:

5182

South Asian (SAS)

AF:

0.0118

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0180

AC:

191

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0106

AC:

722

AN:

68028

Other (OTH)

AF:

0.0241

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

226

452

677

903

1129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0243

Hom.:

Bravo

AF:

0.0339

Asia WGS

AF:

0.0690

AC:

238

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.0

(source)

DANN

Benign

0.21

PhyloP100

-0.75

PromoterAI

0.0049

Neutral

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over