1-201293798-C-T

Variant names:

• chr1-201293798-C-T
• rs80236517
• NM_001005337.3:c.203-144C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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 -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 VariationId 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.

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.203-144C>T		intron	N/A	NP_001005337.1	Q13835-2
	PKP1	NM_000299.4		c.203-144C>T		intron	N/A	NP_000290.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP1	ENST00000367324.8	TSL:1 MANE Select	c.203-144C>T		intron	N/A	ENSP00000356293.4	Q13835-2
	PKP1	ENST00000263946.7	TSL:5	c.203-144C>T		intron	N/A	ENSP00000263946.3	Q13835-1
	PKP1	ENST00000352845.3	TSL:5	c.203-144C>T		intron	N/A	ENSP00000295597.3	Q13835-1

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

African (AFR) AF: 0.0585 AC: 905 AN: 15472

American (AMR) AF: 0.00284 AC: 97 AN: 34198

Ashkenazi Jewish (ASJ) AF: 0.000258 AC: 5 AN: 19356

East Asian (EAS) AF: 0.00 AC: 0 AN: 31532

South Asian (SAS) AF: 0.000296 AC: 18 AN: 60902

European-Finnish (FIN) AF: 0.0000242 AC: 1 AN: 41262

Middle Eastern (MID) AF: 0.00290 AC: 8 AN: 2760

European-Non Finnish (NFE) AF: 0.000209 AC: 65 AN: 310564

Other (OTH) AF: 0.00482 AC: 143 AN: 29672

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

African (AFR) AF: 0.0601 AC: 2496 AN: 41556

American (AMR) AF: 0.00725 AC: 111 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68022

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0146 Hom.: 9

Bravo AF: 0.0199

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.7
DANN	Benign	0.77
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism

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: rs80236517; hg19: chr1-201262926;