chr1-201294002-A-G

Position:

chr1-201294002-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001005337.3(PKP1):c.263A>G(p.Tyr88Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00178 in 1,613,678 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

PKP1
NM_001005337.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.88

Variant links:

Genes affected

PKP1 (HGNC:9023): (plakophilin 1) 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 be involved in molecular recruitment and stabilization during desmosome formation. Mutations in this gene have been associated with the ectodermal dysplasia/skin fragility syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

PKP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.114398986).

BP6

Variant 1-201294002-A-G is Benign according to our data. Variant chr1-201294002-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294802.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00114 (173/152166) while in subpopulation NFE AF= 0.00198 (135/68022). AF 95% confidence interval is 0.00171. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP1	NM_001005337.3 linkuse as main transcript	c.263A>G	p.Tyr88Cys	missense_variant	2/14	ENST00000367324.8
PKP1	NM_000299.4 linkuse as main transcript	c.263A>G	p.Tyr88Cys	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP1	ENST00000367324.8 linkuse as main transcript	c.263A>G	p.Tyr88Cys	missense_variant	2/14	1	NM_001005337.3	P1	Q13835-2
PKP1	ENST00000263946.7 linkuse as main transcript	c.263A>G	p.Tyr88Cys	missense_variant	2/15	5			Q13835-1
PKP1	ENST00000352845.3 linkuse as main transcript	c.263A>G	p.Tyr88Cys	missense_variant	2/14	5			Q13835-1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00103

AC:

258

AN:

251130

Hom.:

AF XY:

0.000987

AC XY:

134

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00175

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00185

AC:

2699

AN:

1461512

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1280

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00291

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.00221

Gnomad4 OTH exome

AF:

0.00200

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152166

Hom.:

Cov.:

AF XY:

0.000834

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00198

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.00163

Hom.:

Bravo

AF:

0.00119

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00104

AC:

126

EpiCase

AF:

0.00174

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Epidermolysis bullosa simplex due to plakophilin deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;D;.

M_CAP

Benign

0.061

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.81

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.048

D;D;D

Sift4G

Benign

0.16

T;T;T

Polyphen

1.0

D;P;P

Vest4

0.84

MVP

0.89

MPC

0.42

ClinPred

0.063

GERP RS

5.8

Varity_R

0.15

gMVP

0.41

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