1-201283573-A-G

Variant names:

• chr1-201283573-A-G
• rs861275
• NM_001005337.3:c.-130A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001005337.3(PKP1):​c.-130A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 152,008 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000026 (0 hom., cov: 33)
• Consequence: PKP1 NM_001005337.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.501
• Publications: 9 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: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005337.3. 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.-130A>G		5_prime_UTR	Exon 1 of 14	NP_001005337.1	Q13835-2
	PKP1	NM_000299.4		c.-130A>G		5_prime_UTR	Exon 1 of 15	NP_000290.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP1	ENST00000367324.8	TSL:1 MANE Select	c.-130A>G		5_prime_UTR	Exon 1 of 14	ENSP00000356293.4	Q13835-2
	PKP1	ENST00000263946.7	TSL:5	c.-130A>G		5_prime_UTR	Exon 1 of 15	ENSP00000263946.3	Q13835-1
	PKP1	ENST00000352845.3	TSL:5	c.-130A>G		upstream_gene	N/A	ENSP00000295597.3	Q13835-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152008 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 9

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152008 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74230

African (AFR) AF: 0.0000967 AC: 4 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 2060

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.5
DANN	Benign	0.83
PhyloP100		-0.50
PromoterAI		0.18	Neutral

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: rs861275; hg19: chr1-201252701;