16-4883623-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5032G>C (p.G1678R) alteration is located in exon 22 (coding exon 22) of the PPL gene. This alteration results from a G to C 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	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.89	D;.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.9	D;.;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.026	D;.;.
Sift4G	Benign	0.11	T;T;.
Polyphen		0.74	P;.;.
Vest4		0.53
MutPred		0.68		Gain of MoRF binding (P = 0.0422);.;.;
MVP		0.93
MPC		0.042
ClinPred		0.94	D
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-4933624;