1-201283991-C-G

Position:

• chr1-201283991-C-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP1	NM_001005337.3	c.202+87C>G		intron_variant		ENST00000367324.8	NP_001005337.1
PKP1	NM_000299.4	c.202+87C>G		intron_variant			NP_000290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP1	ENST00000367324.8	c.202+87C>G		intron_variant		1	NM_001005337.3	ENSP00000356293	P1
PKP1	ENST00000263946.7	c.202+87C>G		intron_variant		5		ENSP00000263946
PKP1	ENST00000352845.3	c.202+87C>G		intron_variant		5		ENSP00000295597

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

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.0635

Gnomad4 ASJ exome AF: 0.0996

Gnomad4 EAS exome AF: 0.000139

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.0719

Gnomad4 NFE exome AF: 0.0808

Gnomad4 OTH exome AF: 0.0866

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

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.0888

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0338

Gnomad4 FIN AF: 0.0655

Gnomad4 NFE AF: 0.0848

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0931 Hom.: 88

Bravo AF: 0.0984

Asia WGS AF: 0.0350 AC: 121 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs12083583; hg19: chr1-201253119;