16-4883707-G-A

Variant names:

Variant summary

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

The NM_002705.5(PPL):c.4948C>T(p.Arg1650Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,960 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PPL
NM_002705.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

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.4948C>T	p.Arg1650Trp	missense_variant	Exon 22 of 22	ENST00000345988.7	NP_002696.4	O60437
PPL	XM_017023374.3 link	c.5035C>T	p.Arg1679Trp	missense_variant	Exon 22 of 22		XP_016878863.1
PPL	XM_017023375.3 link	c.4996C>T	p.Arg1666Trp	missense_variant	Exon 22 of 22		XP_016878864.1
PPL	XM_006720902.5 link	c.4987C>T	p.Arg1663Trp	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.4948C>T	p.Arg1650Trp	missense_variant	Exon 22 of 22	1	NM_002705.5	ENSP00000340510.2	O60437
PPL	ENST00000590782.6 link	c.4942C>T	p.Arg1648Trp	missense_variant	Exon 22 of 22	5		ENSP00000465640.1	K7EKI8
PPL	ENST00000592772.1 link	c.3211C>T	p.Arg1071Trp	missense_variant	Exon 10 of 10	5		ENSP00000467699.1	K7EQ71

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251136

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4948C>T (p.R1650W) alteration is located in exon 22 (coding exon 22) of the PPL gene. This alteration results from a C to T substitution at nucleotide position 4948, causing the arginine (R) at amino acid position 1650 to be replaced by a tryptophan (W). 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

Uncertain

0.44

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.;T

Eigen

Benign

0.0011

Eigen_PC

Benign

-0.098

FATHMM_MKL

Uncertain

0.78

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.8

M;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.0

D;.;.

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.87

MutPred

0.37

Loss of disorder (P = 0.0025);.;.;

MVP

0.65

MPC

0.16

ClinPred

0.98

GERP RS

-2.1

Varity_R

0.74

gMVP

0.78

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