16-4883623-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002705.5(PPL):c.5032G>A(p.Gly1678Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,614,168 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

PPL
NM_002705.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.05

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPL	NM_002705.5 link	c.5032G>A	p.Gly1678Arg	missense_variant	Exon 22 of 22	ENST00000345988.7	NP_002696.4	O60437
PPL	XM_017023374.3 link	c.5119G>A	p.Gly1707Arg	missense_variant	Exon 22 of 22		XP_016878863.1
PPL	XM_017023375.3 link	c.5080G>A	p.Gly1694Arg	missense_variant	Exon 22 of 22		XP_016878864.1
PPL	XM_006720902.5 link	c.5071G>A	p.Gly1691Arg	missense_variant	Exon 22 of 22		XP_006720965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PPL	ENST00000345988.7 link	c.5032G>A	p.Gly1678Arg	missense_variant	Exon 22 of 22	1	NM_002705.5	ENSP00000340510.2	O60437
PPL	ENST00000590782.6 link	c.5026G>A	p.Gly1676Arg	missense_variant	Exon 22 of 22	5		ENSP00000465640.1	K7EKI8
PPL	ENST00000592772.1 link	c.3295G>A	p.Gly1099Arg	missense_variant	Exon 10 of 10	5		ENSP00000467699.1	K7EQ71

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251396

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5032G>A (p.G1678R) 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 5032, causing the glycine (G) at amino acid position 1678 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.89

D;.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.061

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Uncertain

0.044

MutationAssessor

Pathogenic

3.0

M;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.9

D;.;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.026

D;.;.

Sift4G

Benign

0.11

T;T;.

Polyphen

0.87

P;.;.

Vest4

0.53

MutPred

0.68

Gain of MoRF binding (P = 0.0422);.;.;

MVP

0.93

MPC

0.042

ClinPred

0.65

GERP RS

3.7

Varity_R

0.65

gMVP

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