NM_002705.5:c.5247G>C

Variant names:

• chr16-4883408-C-G
• rs116861592
• NM_002705.5:c.5247G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002705.5(PPL):​c.5247G>C​(p.Ala1749Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,614,144 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (16 hom.)
• Consequence: PPL NM_002705.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.85
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-4883408-C-G is Benign according to our data. Variant chr16-4883408-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2646162.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 gene

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.5247G>C	p.Ala1749Ala	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.5247G>C	p.Ala1749Ala	synonymous	Exon 22 of 22	ENSP00000340510.2	O60437
	PPL	ENST00000950847.1		c.5295G>C	p.Ala1765Ala	synonymous	Exon 22 of 22	ENSP00000620906.1
	PPL	ENST00000923224.1		c.5244G>C	p.Ala1748Ala	synonymous	Exon 22 of 22	ENSP00000593283.1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00317

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00226 AC: 569 AN: 251354 AF XY: 0.00238

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00204

Gnomad NFE exome AF: 0.00368

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00305 AC: 4455 AN: 1461830 Hom.: 16 Cov.: 34 AF XY: 0.00299 AC XY: 2171 AN XY: 727222

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00197 AC: 88 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000870 AC: 75 AN: 86252

European-Finnish (FIN) AF: 0.00234 AC: 125 AN: 53384

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00353 AC: 3920 AN: 1112004

Other (OTH) AF: 0.00371 AC: 224 AN: 60394

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74496

African (AFR) AF: 0.000650 AC: 27 AN: 41564

American (AMR) AF: 0.00405 AC: 62 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00318 AC: 216 AN: 68030

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00210 Hom.: 0

Bravo AF: 0.00277

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.074
DANN	Benign	0.72
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism

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: rs116861592; hg19: chr16-4933409;