1-201283991-C-G

Variant names:

• chr1-201283991-C-G
• rs12083583
• NM_001005337.3:c.202+87C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005337.3(PKP1):​c.202+87C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0787 in 1,241,658 control chromosomes in the GnomAD database, including 4,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (784 hom., cov: 33)
  • Exomes 𝑓: 0.076 (3527 hom.)
• Consequence: PKP1 NM_001005337.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.34
• Publications: 0 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-201283991-C-G is Benign according to our data. Variant chr1-201283991-C-G is described in ClinVar as Benign. ClinVar VariationId is 1222960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

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.202+87C>G		intron	N/A	NP_001005337.1	Q13835-2
	PKP1	NM_000299.4		c.202+87C>G		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.202+87C>G		intron	N/A	ENSP00000356293.4	Q13835-2
	PKP1	ENST00000263946.7	TSL:5	c.202+87C>G		intron	N/A	ENSP00000263946.3	Q13835-1
	PKP1	ENST00000352845.3	TSL:5	c.202+87C>G		intron	N/A	ENSP00000295597.3	Q13835-1

Frequencies

GnomAD3 genomes AF: 0.0951 AC: 14469 AN: 152072 Hom.: 779 Cov.: 33

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0890

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0655

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0848

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.0764 AC: 83184 AN: 1089468 Hom.: 3527 AF XY: 0.0754 AC XY: 41771 AN XY: 553968

African (AFR) AF: 0.141 AC: 3644 AN: 25834

American (AMR) AF: 0.0635 AC: 2459 AN: 38714

Ashkenazi Jewish (ASJ) AF: 0.0996 AC: 2322 AN: 23324

East Asian (EAS) AF: 0.000139 AC: 5 AN: 35916

South Asian (SAS) AF: 0.0378 AC: 2858 AN: 75516

European-Finnish (FIN) AF: 0.0719 AC: 3503 AN: 48698

Middle Eastern (MID) AF: 0.106 AC: 517 AN: 4866

European-Non Finnish (NFE) AF: 0.0808 AC: 63710 AN: 788514

Other (OTH) AF: 0.0866 AC: 4166 AN: 48086

GnomAD4 genome AF: 0.0952 AC: 14495 AN: 152190 Hom.: 784 Cov.: 33 AF XY: 0.0938 AC XY: 6982 AN XY: 74416

African (AFR) AF: 0.139 AC: 5762 AN: 41530

American (AMR) AF: 0.0888 AC: 1358 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 373 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0338 AC: 163 AN: 4826

European-Finnish (FIN) AF: 0.0655 AC: 694 AN: 10600

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.0848 AC: 5766 AN: 67988

Other (OTH) AF: 0.110 AC: 232 AN: 2106

Alfa AF: 0.0931 Hom.: 88

Bravo AF: 0.0984

Asia WGS AF: 0.0350 AC: 121 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.29
PhyloP100		-2.3
PromoterAI		0.068	Neutral
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: rs12083583; hg19: chr1-201253119;