chr16-4885145-C-T

Variant names:

• chr16-4885145-C-T
• rs1049206
• NM_002705.5:c.3510G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002705.5(PPL):​c.3510G>A​(p.Val1170Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,613,822 control chromosomes in the GnomAD database, including 80,409 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (7748 hom., cov: 31)
  • Exomes 𝑓: 0.31 (72661 hom.)
• Consequence: PPL NM_002705.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246
• Publications: 15 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP7: Synonymous conserved (PhyloP=-0.246 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

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.3510G>A	p.Val1170Val	synonymous	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.3510G>A	p.Val1170Val	synonymous	Exon 22 of 22	ENSP00000340510.2	O60437
	PPL	ENST00000950847.1		c.3558G>A	p.Val1186Val	synonymous	Exon 22 of 22	ENSP00000620906.1
	PPL	ENST00000923224.1		c.3507G>A	p.Val1169Val	synonymous	Exon 22 of 22	ENSP00000593283.1

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47792 AN: 151944 Hom.: 7726 Cov.: 31

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.346

GnomAD2 exomes AF: 0.334 AC: 83999 AN: 251340 AF XY: 0.335

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.295

Gnomad FIN exome AF: 0.256

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.311 AC: 453900 AN: 1461760 Hom.: 72661 Cov.: 85 AF XY: 0.314 AC XY: 228572 AN XY: 727192

African (AFR) AF: 0.342 AC: 11445 AN: 33480

American (AMR) AF: 0.384 AC: 17182 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 11311 AN: 26136

East Asian (EAS) AF: 0.315 AC: 12486 AN: 39700

South Asian (SAS) AF: 0.458 AC: 39529 AN: 86258

European-Finnish (FIN) AF: 0.259 AC: 13788 AN: 53294

Middle Eastern (MID) AF: 0.333 AC: 1921 AN: 5768

European-Non Finnish (NFE) AF: 0.294 AC: 326398 AN: 1112006

Other (OTH) AF: 0.329 AC: 19840 AN: 60394

GnomAD4 genome AF: 0.315 AC: 47855 AN: 152062 Hom.: 7748 Cov.: 31 AF XY: 0.317 AC XY: 23562 AN XY: 74328

African (AFR) AF: 0.339 AC: 14056 AN: 41466

American (AMR) AF: 0.343 AC: 5244 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1511 AN: 3470

East Asian (EAS) AF: 0.303 AC: 1561 AN: 5148

South Asian (SAS) AF: 0.473 AC: 2275 AN: 4812

European-Finnish (FIN) AF: 0.243 AC: 2579 AN: 10604

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19639 AN: 67970

Other (OTH) AF: 0.346 AC: 730 AN: 2110

Alfa AF: 0.311 Hom.: 14687

Bravo AF: 0.322

Asia WGS AF: 0.422 AC: 1465 AN: 3478

EpiCase AF: 0.302

EpiControl AF: 0.314

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.5
DANN	Benign	0.90
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1049206; hg19: chr16-4935146; COSMIC: COSV52165750; COSMIC: COSV52165750;