chr1-201293798-C-T

Position:

• chr1-201293798-C-T

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.203-144C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 698,018 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (74 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (26 hom.)
• Consequence: PKP1 NM_001005337.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.649

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=-0.85).
• BP6: Variant 1-201293798-C-T is Benign according to our data. Variant chr1-201293798-C-T is described in ClinVar as [Benign]. Clinvar id is 1275145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP1	NM_001005337.3	c.203-144C>T		intron_variant		ENST00000367324.8	NP_001005337.1
PKP1	NM_000299.4	c.203-144C>T		intron_variant			NP_000290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP1	ENST00000367324.8	c.203-144C>T		intron_variant		1	NM_001005337.3	ENSP00000356293	P1
PKP1	ENST00000263946.7	c.203-144C>T		intron_variant		5		ENSP00000263946
PKP1	ENST00000352845.3	c.203-144C>T		intron_variant		5		ENSP00000295597

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2652 AN: 152182 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00228 AC: 1242 AN: 545718 Hom.: 26 AF XY: 0.00178 AC XY: 524 AN XY: 294196

Gnomad4 AFR exome AF: 0.0585

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.000258

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000296

Gnomad4 FIN exome AF: 0.0000242

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.00482

GnomAD4 genome AF: 0.0175 AC: 2660 AN: 152300 Hom.: 74 Cov.: 32 AF XY: 0.0171 AC XY: 1276 AN XY: 74462

Gnomad4 AFR AF: 0.0601

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0146 Hom.: 9

Bravo AF: 0.0199

Asia WGS AF: 0.00635 AC: 22 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 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.7
DANN	Benign	0.77

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: rs80236517; hg19: chr1-201262926;