chr16-4883685-G-C

Position:

• chr16-4883685-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002705.5(PPL):​c.4970C>G​(p.Ser1657Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.94

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.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity PEPL_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPL	NM_002705.5	c.4970C>G	p.Ser1657Cys	missense_variant	22/22	ENST00000345988.7	NP_002696.4
PPL	XM_017023374.3	c.5057C>G	p.Ser1686Cys	missense_variant	22/22		XP_016878863.1
PPL	XM_017023375.3	c.5018C>G	p.Ser1673Cys	missense_variant	22/22		XP_016878864.1
PPL	XM_006720902.5	c.5009C>G	p.Ser1670Cys	missense_variant	22/22		XP_006720965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPL	ENST00000345988.7	c.4970C>G	p.Ser1657Cys	missense_variant	22/22	1	NM_002705.5	ENSP00000340510	P3
PPL	ENST00000590782.6	c.4964C>G	p.Ser1655Cys	missense_variant	22/22	5		ENSP00000465640	A1
PPL	ENST00000592772.1	c.3233C>G	p.Ser1078Cys	missense_variant	10/10	5		ENSP00000467699

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

The c.4970C>G (p.S1657C) alteration is located in exon 22 (coding exon 22) of the PPL gene. This alteration results from a C to G substitution at nucleotide position 4970, causing the serine (S) at amino acid position 1657 to be replaced by a cysteine (C). 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	0.33
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.2	D;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.016	D;.;.
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.80
MutPred		0.48		Loss of disorder (P = 0.0172);.;.;
MVP		0.64
MPC		0.16
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.65
gMVP		0.45

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: chr16-4933686;