1-201293980-G-A

Position:

chr1-201293980-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001005337.3(PKP1):c.241G>A(p.Gly81Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,613,888 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G81E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00088 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 5 hom. )

Consequence

PKP1
NM_001005337.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.88

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040651143).

BP6

Variant 1-201293980-G-A is Benign according to our data. Variant chr1-201293980-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294801.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00088 (134/152258) while in subpopulation NFE AF= 0.000632 (43/68020). AF 95% confidence interval is 0.000482. There are 1 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP1	NM_001005337.3 linkuse as main transcript	c.241G>A	p.Gly81Arg	missense_variant	2/14	ENST00000367324.8	NP_001005337.1	Q13835-2A0A024R952
PKP1	NM_000299.4 linkuse as main transcript	c.241G>A	p.Gly81Arg	missense_variant	2/15		NP_000290.2	Q13835-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PKP1	ENST00000367324.8 linkuse as main transcript	c.241G>A	p.Gly81Arg	missense_variant	2/14	1	NM_001005337.3	ENSP00000356293.4	Q13835-2
PKP1	ENST00000263946.7 linkuse as main transcript	c.241G>A	p.Gly81Arg	missense_variant	2/15	5		ENSP00000263946.3	Q13835-1
PKP1	ENST00000352845.3 linkuse as main transcript	c.241G>A	p.Gly81Arg	missense_variant	2/14	5		ENSP00000295597.3	Q13835-1

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

134

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00123

AC:

308

AN:

250990

Hom.:

AF XY:

0.00109

AC XY:

148

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000984

Gnomad ASJ exome

AF:

0.0153

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000960

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00105

AC:

1539

AN:

1461630

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

749

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.0181

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000814

Gnomad4 OTH exome

AF:

0.00181

GnomAD4 genome

AF:

0.000880

AC:

134

AN:

152258

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00101

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00106

AC:

129

EpiCase

AF:

0.00104

EpiControl

AF:

0.000949

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

.;T;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.66

T;T;.

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.041

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.81

L;L;L

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.88

MutPred

0.49

Gain of MoRF binding (P = 0.0148);Gain of MoRF binding (P = 0.0148);Gain of MoRF binding (P = 0.0148);

MVP

0.90

MPC

0.51

ClinPred

0.074

GERP RS

5.6

Varity_R

0.23

gMVP

0.44

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