chr1-201316584-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005337.3(PKP1):​c.733C>A​(p.Leu245Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L245L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKP1 NM_001005337.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07841164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP1	NM_001005337.3	c.733C>A	p.Leu245Met	missense_variant	Exon 4 of 14	ENST00000367324.8	NP_001005337.1
PKP1	NM_000299.4	c.733C>A	p.Leu245Met	missense_variant	Exon 4 of 15		NP_000290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP1	ENST00000367324.8	c.733C>A	p.Leu245Met	missense_variant	Exon 4 of 14	1	NM_001005337.3	ENSP00000356293.4
PKP1	ENST00000263946.7	c.733C>A	p.Leu245Met	missense_variant	Exon 4 of 15	5		ENSP00000263946.3
PKP1	ENST00000352845.3	c.733C>A	p.Leu245Met	missense_variant	Exon 4 of 14	5		ENSP00000295597.3
PKP1	ENST00000475988.1	n.75C>A		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 245502 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.18
DEOGEN2	Benign	0.023	.;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.010
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.58	T;T;.
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		2.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.81	N;N;N
REVEL	Benign	0.091
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.042	B;B;B
Vest4		0.23
MutPred		0.40		Loss of catalytic residue at L245 (P = 0.0189);Loss of catalytic residue at L245 (P = 0.0189);Loss of catalytic residue at L245 (P = 0.0189);
MVP		0.72
MPC		0.10
ClinPred		0.16	T
GERP RS		3.9
Varity_R		0.19
gMVP		0.22
Mutation Taster		=89/11	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: rs7514146; hg19: chr1-201285712;