PPL p.Gly1678Arg

Variant names:

• chr16-4883623-C-G
• NM_002705.5:c.5032G>C
• PPL p.Gly1678Arg

Your query was ambiguous. Multiple possible variants found:

• chr16-4883623-C-G
• chr16-4883623-C-T
• chr16-4883621-CCC-ACG
• chr16-4883621-CCC-GCG
• chr16-4883621-CCC-TCG
• chr16-4883621-CCC-TCT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002705.5(PPL):​c.5032G>C​(p.Gly1678Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPL NM_002705.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002705.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPL	NM_002705.5	MANE Select	c.5032G>C	p.Gly1678Arg	missense	Exon 22 of 22	NP_002696.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPL	ENST00000345988.7	TSL:1 MANE Select	c.5032G>C	p.Gly1678Arg	missense	Exon 22 of 22	ENSP00000340510.2	O60437
	PPL	ENST00000950847.1		c.5080G>C	p.Gly1694Arg	missense	Exon 22 of 22	ENSP00000620906.1
	PPL	ENST00000923224.1		c.5029G>C	p.Gly1677Arg	missense	Exon 22 of 22	ENSP00000593283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.026	D
Sift4G	Benign	0.11	T
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-4933624;