16-4883874-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_002705.5(PPL):c.4781G>A(p.Arg1594Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,614,022 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 1 hom. )

Consequence

PPL
NM_002705.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.565

Variant links:

Genes affected

PPL (HGNC:9273): (periplakin) The protein encoded by this gene is a component of desmosomes and of the epidermal cornified envelope in keratinocytes. The N-terminal domain of this protein interacts with the plasma membrane and its C-terminus interacts with intermediate filaments. Through its rod domain, this protein forms complexes with envoplakin. This protein may serve as a link between the cornified envelope and desmosomes as well as intermediate filaments. AKT1/PKB, a protein kinase mediating a variety of cell growth and survival signaling processes, is reported to interact with this protein, suggesting a possible role for this protein as a localization signal in AKT1-mediated signaling. [provided by RefSeq, Jul 2008]

PPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0076697767).

BP6

Variant 16-4883874-C-T is Benign according to our data. Variant chr16-4883874-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3025425.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PPL	NM_002705.5 linkuse as main transcript	c.4781G>A	p.Arg1594Gln	missense_variant	22/22	ENST00000345988.7
PPL	XM_017023374.3 linkuse as main transcript	c.4868G>A	p.Arg1623Gln	missense_variant	22/22
PPL	XM_017023375.3 linkuse as main transcript	c.4829G>A	p.Arg1610Gln	missense_variant	22/22
PPL	XM_006720902.5 linkuse as main transcript	c.4820G>A	p.Arg1607Gln	missense_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PPL	ENST00000345988.7 linkuse as main transcript	c.4781G>A	p.Arg1594Gln	missense_variant	22/22	1	NM_002705.5	P3
PPL	ENST00000590782.6 linkuse as main transcript	c.4775G>A	p.Arg1592Gln	missense_variant	22/22	5		A1
PPL	ENST00000592772.1 linkuse as main transcript	c.3044G>A	p.Arg1015Gln	missense_variant	10/10	5

Frequencies

GnomAD3 genomes

AF:

0.000716

AC:

109

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000442

AC:

111

AN:

251234

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000487

AC:

712

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

340

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.000962

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000488

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.000715

AC:

109

AN:

152348

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00139

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000544

Hom.:

Bravo

AF:

0.000880

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.4781G>A (p.R1594Q) alteration is located in exon 22 (coding exon 22) of the PPL gene. This alteration results from a G to A substitution at nucleotide position 4781, causing the arginine (R) at amino acid position 1594 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

PPL: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Benign

0.84

DEOGEN2

Benign

0.12

T;.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.0077

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.;.

MutationTaster

Benign

0.90

N;N

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.55

N;.;.

REVEL

Benign

0.036

Sift

Benign

0.64

T;.;.

Sift4G

Benign

0.15

T;T;.

Polyphen

0.11

B;.;.

Vest4

0.074

MVP

0.61

MPC

0.020

ClinPred

0.00070

GERP RS

3.9

Varity_R

0.038

gMVP

0.15

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