1-201283738-C-T

Variant names:

• chr1-201283738-C-T
• rs2268147
• NM_001005337.3:c.36C>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.36C>T​(p.Tyr12Tyr) 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
• Publications: 16 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=-0.43).
• BP6: Variant 1-201283738-C-T is Benign according to our data. Variant chr1-201283738-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

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.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 14	NP_001005337.1	Q13835-2
	PKP1	NM_000299.4		c.36C>T	p.Tyr12Tyr	synonymous	Exon 1 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.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 14	ENSP00000356293.4	Q13835-2
	PKP1	ENST00000263946.7	TSL:5	c.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 15	ENSP00000263946.3	Q13835-1
	PKP1	ENST00000352845.3	TSL:5	c.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 14	ENSP00000295597.3	Q13835-1

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

GnomAD2 exomes AF: 0.116 AC: 29039 AN: 250988 AF XY: 0.113

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 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

African (AFR) AF: 0.347 AC: 11603 AN: 33466

American (AMR) AF: 0.0969 AC: 4335 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2896 AN: 26128

East Asian (EAS) AF: 0.0781 AC: 3100 AN: 39692

South Asian (SAS) AF: 0.150 AC: 12915 AN: 86248

European-Finnish (FIN) AF: 0.130 AC: 6918 AN: 53394

Middle Eastern (MID) AF: 0.0825 AC: 476 AN: 5768

European-Non Finnish (NFE) AF: 0.0842 AC: 93645 AN: 1111844

Other (OTH) AF: 0.109 AC: 6584 AN: 60384

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

African (AFR) AF: 0.340 AC: 14091 AN: 41482

American (AMR) AF: 0.115 AC: 1763 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 411 AN: 3470

East Asian (EAS) AF: 0.0801 AC: 415 AN: 5178

South Asian (SAS) AF: 0.154 AC: 743 AN: 4826

European-Finnish (FIN) AF: 0.135 AC: 1433 AN: 10612

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.0861 AC: 5853 AN: 68008

Other (OTH) AF: 0.127 AC: 269 AN: 2114

Alfa AF: 0.110 Hom.: 2894

Bravo AF: 0.167

Asia WGS AF: 0.159 AC: 554 AN: 3478

EpiCase AF: 0.0839

EpiControl AF: 0.0841

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		0.82
PromoterAI		-0.046	Neutral
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: rs2268147; hg19: chr1-201252866; COSMIC: COSV55825976;