1-201317643-C-T

Variant names:

• chr1-201317643-C-T
• rs1722779
• NM_001005337.3:c.918C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001005337.3(PKP1):​c.918C>T​(p.Ala306Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,613,656 control chromosomes in the GnomAD database, including 34,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2818 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32099 hom.)
• Consequence: PKP1 NM_001005337.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -8.92
• Publications: 13 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: Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-201317643-C-T is Benign according to our data. Variant chr1-201317643-C-T is described in ClinVar as Benign. ClinVar VariationId is 256862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP1	NM_001005337.3	c.918C>T	p.Ala306Ala	synonymous_variant	Exon 5 of 14	ENST00000367324.8	NP_001005337.1
PKP1	NM_000299.4	c.918C>T	p.Ala306Ala	synonymous_variant	Exon 5 of 15		NP_000290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP1	ENST00000367324.8	c.918C>T	p.Ala306Ala	synonymous_variant	Exon 5 of 14	1	NM_001005337.3	ENSP00000356293.4
PKP1	ENST00000263946.7	c.918C>T	p.Ala306Ala	synonymous_variant	Exon 5 of 15	5		ENSP00000263946.3
PKP1	ENST00000352845.3	c.918C>T	p.Ala306Ala	synonymous_variant	Exon 5 of 14	5		ENSP00000295597.3
PKP1	ENST00000475988.1	n.260C>T		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28382 AN: 151992 Hom.: 2807 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.196 AC: 48831 AN: 249448 AF XY: 0.193

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.227

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.206 AC: 301799 AN: 1461548 Hom.: 32099 Cov.: 36 AF XY: 0.204 AC XY: 148058 AN XY: 727086

African (AFR) AF: 0.141 AC: 4711 AN: 33474

American (AMR) AF: 0.225 AC: 10046 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 4173 AN: 26132

East Asian (EAS) AF: 0.236 AC: 9353 AN: 39698

South Asian (SAS) AF: 0.116 AC: 9974 AN: 86248

European-Finnish (FIN) AF: 0.178 AC: 9469 AN: 53306

Middle Eastern (MID) AF: 0.207 AC: 1193 AN: 5766

European-Non Finnish (NFE) AF: 0.217 AC: 241304 AN: 1111836

Other (OTH) AF: 0.192 AC: 11576 AN: 60388

GnomAD4 genome AF: 0.187 AC: 28441 AN: 152108 Hom.: 2818 Cov.: 32 AF XY: 0.184 AC XY: 13700 AN XY: 74368

African (AFR) AF: 0.141 AC: 5867 AN: 41502

American (AMR) AF: 0.203 AC: 3109 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 534 AN: 3472

East Asian (EAS) AF: 0.229 AC: 1178 AN: 5150

South Asian (SAS) AF: 0.118 AC: 567 AN: 4822

European-Finnish (FIN) AF: 0.176 AC: 1864 AN: 10600

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14455 AN: 67958

Other (OTH) AF: 0.201 AC: 426 AN: 2116

Alfa AF: 0.199 Hom.: 2031

Bravo AF: 0.193

Asia WGS AF: 0.188 AC: 655 AN: 3478

EpiCase AF: 0.216

EpiControl AF: 0.217

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.70
CADD	Benign	0.42
DANN	Benign	0.71
PhyloP100		-8.9
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: rs1722779; hg19: chr1-201286771; COSMIC: COSV55822925;