NM_001005337.3:c.733C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 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: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005337.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP1	NM_001005337.3	MANE Select	c.733C>T	p.Leu245Leu	synonymous	Exon 4 of 14	NP_001005337.1	Q13835-2
	PKP1	NM_000299.4		c.733C>T	p.Leu245Leu	synonymous	Exon 4 of 15	NP_000290.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP1	ENST00000367324.8	TSL:1 MANE Select	c.733C>T	p.Leu245Leu	synonymous	Exon 4 of 14	ENSP00000356293.4	Q13835-2
	PKP1	ENST00000263946.7	TSL:5	c.733C>T	p.Leu245Leu	synonymous	Exon 4 of 15	ENSP00000263946.3	Q13835-1
	PKP1	ENST00000352845.3	TSL:5	c.733C>T	p.Leu245Leu	synonymous	Exon 4 of 14	ENSP00000295597.3	Q13835-1

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

GnomAD2 exomes AF: 0.105 AC: 25851 AN: 245502 AF XY: 0.107

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 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

African (AFR) AF: 0.280 AC: 9356 AN: 33406

American (AMR) AF: 0.0669 AC: 2967 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3136 AN: 26018

East Asian (EAS) AF: 0.0253 AC: 1003 AN: 39670

South Asian (SAS) AF: 0.169 AC: 14449 AN: 85332

European-Finnish (FIN) AF: 0.114 AC: 6068 AN: 53270

Middle Eastern (MID) AF: 0.136 AC: 772 AN: 5678

European-Non Finnish (NFE) AF: 0.0871 AC: 96663 AN: 1110330

Other (OTH) AF: 0.109 AC: 6576 AN: 60284

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

African (AFR) AF: 0.277 AC: 11508 AN: 41526

American (AMR) AF: 0.0969 AC: 1483 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 425 AN: 3472

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5174

South Asian (SAS) AF: 0.180 AC: 867 AN: 4828

European-Finnish (FIN) AF: 0.102 AC: 1085 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0906 AC: 6161 AN: 67996

Other (OTH) AF: 0.133 AC: 280 AN: 2112

Alfa AF: 0.105 Hom.: 4628

Bravo AF: 0.146

Asia WGS AF: 0.100 AC: 347 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Epidermolysis bullosa simplex due to plakophilin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		2.1
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: rs7514146; hg19: chr1-201285712;