1-201289391-A-T

Variant names:

• chr1-201289391-A-T
• rs832174
• NM_001005337.3:c.203-4551A>T

Variant summary

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

The NM_000299.4(PKP1):​c.203-4551A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 152,158 control chromosomes in the GnomAD database, including 36,332 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 0.66 (36332 hom., cov: 32)
• Consequence: PKP1 NM_000299.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38
• Publications: 5 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000299.4. 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
	PKP1	NM_001005337.3	MANE Select	c.203-4551A>T		intron	N/A	NP_001005337.1
	PKP1	NM_000299.4		c.203-4551A>T		intron	N/A	NP_000290.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP1	ENST00000367324.8	TSL:1 MANE Select	c.203-4551A>T		intron	N/A	ENSP00000356293.4
	PKP1	ENST00000263946.7	TSL:5	c.203-4551A>T		intron	N/A	ENSP00000263946.3
	PKP1	ENST00000352845.3	TSL:5	c.203-4551A>T		intron	N/A	ENSP00000295597.3

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100571 AN: 152040 Hom.: 36318 Cov.: 32

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.748

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.689

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

GnomAD4 genome AF: 0.661 AC: 100612 AN: 152158 Hom.: 36332 Cov.: 32 AF XY: 0.664 AC XY: 49356 AN XY: 74382

African (AFR) AF: 0.339 AC: 14079 AN: 41482

American (AMR) AF: 0.748 AC: 11447 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2356 AN: 3472

East Asian (EAS) AF: 0.914 AC: 4731 AN: 5178

South Asian (SAS) AF: 0.745 AC: 3588 AN: 4818

European-Finnish (FIN) AF: 0.754 AC: 7981 AN: 10586

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.796 AC: 54099 AN: 68006

Other (OTH) AF: 0.688 AC: 1455 AN: 2116

Alfa AF: 0.770 Hom.: 22694

Bravo AF: 0.649

Asia WGS AF: 0.775 AC: 2695 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.080
DANN	Benign	0.47
PhyloP100		-1.4
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: rs832174; hg19: chr1-201258519;