rs832147

Variant names:

• chr1-201300559-C-G
• rs832147
• NM_001005337.3:c.306+6514C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001005337.3(PKP1):​c.306+6514C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,222 control chromosomes in the GnomAD database, including 2,496 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 0.17 (2496 hom., cov: 33)
• Consequence: PKP1 NM_001005337.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 7 publications found

Genes affected

PKP1 (HGNC:9023): (plakophilin 1) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This protein may be involved in molecular recruitment and stabilization during desmosome formation. Mutations in this gene have been associated with the ectodermal dysplasia/skin fragility syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

PKP1 Gene-Disease associations (from GenCC):

• epidermolysis bullosa simplex due to plakophilin deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP1	NM_001005337.3	c.306+6514C>G		intron_variant	Intron 2 of 13	ENST00000367324.8	NP_001005337.1
PKP1	NM_000299.4	c.306+6514C>G		intron_variant	Intron 2 of 14		NP_000290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP1	ENST00000367324.8	c.306+6514C>G		intron_variant	Intron 2 of 13	1	NM_001005337.3	ENSP00000356293.4
PKP1	ENST00000263946.7	c.306+6514C>G		intron_variant	Intron 2 of 14	5		ENSP00000263946.3
PKP1	ENST00000352845.3	c.306+6514C>G		intron_variant	Intron 2 of 13	5		ENSP00000295597.3

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25671 AN: 152104 Hom.: 2494 Cov.: 33

Gnomad AFR AF: 0.0737

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.191

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.169 AC: 25682 AN: 152222 Hom.: 2496 Cov.: 33 AF XY: 0.167 AC XY: 12412 AN XY: 74430

African (AFR) AF: 0.0738 AC: 3066 AN: 41554

American (AMR) AF: 0.196 AC: 3001 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 522 AN: 3472

East Asian (EAS) AF: 0.237 AC: 1226 AN: 5168

South Asian (SAS) AF: 0.117 AC: 562 AN: 4814

European-Finnish (FIN) AF: 0.179 AC: 1895 AN: 10594

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14570 AN: 67994

Other (OTH) AF: 0.189 AC: 400 AN: 2116

Alfa AF: 0.187 Hom.: 361

Bravo AF: 0.172

Asia WGS AF: 0.183 AC: 636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.33
DANN	Benign	0.78
PhyloP100		-2.3
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: rs832147; hg19: chr1-201269687;