1-201316584-C-T

Variant names:

• chr1-201316584-C-T
• rs7514146
• NM_001005337.3:c.733C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001005337.3(PKP1):​c.733C>T​(p.Leu245Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,610,546 control chromosomes in the GnomAD database, including 10,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2118 hom., cov: 33)
  • Exomes 𝑓: 0.097 (8165 hom.)
• Consequence: PKP1 NM_001005337.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.08

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-201316584-C-T is Benign according to our data. Variant chr1-201316584-C-T is described in ClinVar as [Benign]. Clinvar id is 294810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP1	NM_001005337.3	c.733C>T	p.Leu245Leu	synonymous_variant	Exon 4 of 14	ENST00000367324.8	NP_001005337.1
PKP1	NM_000299.4	c.733C>T	p.Leu245Leu	synonymous_variant	Exon 4 of 15		NP_000290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP1	ENST00000367324.8	c.733C>T	p.Leu245Leu	synonymous_variant	Exon 4 of 14	1	NM_001005337.3	ENSP00000356293.4
PKP1	ENST00000263946.7	c.733C>T	p.Leu245Leu	synonymous_variant	Exon 4 of 15	5		ENSP00000263946.3
PKP1	ENST00000352845.3	c.733C>T	p.Leu245Leu	synonymous_variant	Exon 4 of 14	5		ENSP00000295597.3
PKP1	ENST00000475988.1	n.75C>T		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21909 AN: 152118 Hom.: 2112 Cov.: 33

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0972

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.105 AC: 25851 AN: 245502 Hom.: 1892 AF XY: 0.107 AC XY: 14148 AN XY: 132506

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.0634

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.00794

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0901

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.0967 AC: 140990 AN: 1458310 Hom.: 8165 Cov.: 33 AF XY: 0.0985 AC XY: 71390 AN XY: 725006

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.0669

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.0253

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.0871

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.144 AC: 21941 AN: 152236 Hom.: 2118 Cov.: 33 AF XY: 0.144 AC XY: 10750 AN XY: 74438

Gnomad4 AFR AF: 0.277

Gnomad4 AMR AF: 0.0969

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0906

Gnomad4 OTH AF: 0.133

Alfa AF: 0.101 Hom.: 2160

Bravo AF: 0.146

Asia WGS AF: 0.100 AC: 347 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Epidermolysis bullosa simplex due to plakophilin deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.81

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: rs7514146; hg19: chr1-201285712;