rs2268147

Positions:

• chr1-201283738-C-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.36C>T​(p.Tyr12=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,826 control chromosomes in the GnomAD database, including 11,496 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2957 hom., cov: 33)
  • Exomes 𝑓: 0.097 (8539 hom.)
• Consequence: PKP1 NM_001005337.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.822

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=-0.43).
• BP6: Variant 1-201283738-C-T is Benign according to our data. Variant chr1-201283738-C-T is described in ClinVar as [Benign]. Clinvar id is 256861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.822 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP1	NM_001005337.3	c.36C>T	p.Tyr12=	synonymous_variant	1/14	ENST00000367324.8
PKP1	NM_000299.4	c.36C>T	p.Tyr12=	synonymous_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP1	ENST00000367324.8	c.36C>T	p.Tyr12=	synonymous_variant	1/14	1	NM_001005337.3	P1
PKP1	ENST00000263946.7	c.36C>T	p.Tyr12=	synonymous_variant	1/15	5
PKP1	ENST00000352845.3	c.36C>T	p.Tyr12=	synonymous_variant	1/14	5

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25052 AN: 152068 Hom.: 2952 Cov.: 33

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.0805

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.0861

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.116 AC: 29039 AN: 250988 Hom.: 2310 AF XY: 0.113 AC XY: 15321 AN XY: 135746

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.0928

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.0746

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0844

Gnomad OTH exome AF: 0.0986

GnomAD4 exome AF: 0.0975 AC: 142472 AN: 1461640 Hom.: 8539 Cov.: 33 AF XY: 0.0983 AC XY: 71494 AN XY: 727130

Gnomad4 AFR exome AF: 0.347

Gnomad4 AMR exome AF: 0.0969

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.0781

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.0842

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.165 AC: 25072 AN: 152186 Hom.: 2957 Cov.: 33 AF XY: 0.164 AC XY: 12221 AN XY: 74394

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.0801

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.0861

Gnomad4 OTH AF: 0.127

Alfa AF: 0.104 Hom.: 1960

Bravo AF: 0.167

Asia WGS AF: 0.159 AC: 554 AN: 3478

EpiCase AF: 0.0839

EpiControl AF: 0.0841

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Epidermolysis bullosa simplex due to plakophilin deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.43
CADD	Benign	14
DANN	Benign	0.96

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: rs2268147; hg19: chr1-201252866; COSMIC: COSV55825976;