Variant 1-201293945-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001005337.3(PKP1):c.206C>A(p.Ser69Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PKP1
NM_001005337.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.61

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP1	NM_001005337.3 linkuse as main transcript	c.206C>A	p.Ser69Tyr	missense_variant	2/14	ENST00000367324.8	NP_001005337.1
PKP1	NM_000299.4 linkuse as main transcript	c.206C>A	p.Ser69Tyr	missense_variant	2/15		NP_000290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP1	ENST00000367324.8 linkuse as main transcript	c.206C>A	p.Ser69Tyr	missense_variant	2/14	1	NM_001005337.3	ENSP00000356293	P1	Q13835-2
PKP1	ENST00000263946.7 linkuse as main transcript	c.206C>A	p.Ser69Tyr	missense_variant	2/15	5		ENSP00000263946		Q13835-1
PKP1	ENST00000352845.3 linkuse as main transcript	c.206C>A	p.Ser69Tyr	missense_variant	2/14	5		ENSP00000295597		Q13835-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456394

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724678

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2023

The c.206C>A (p.S69Y) alteration is located in exon 2 (coding exon 2) of the PKP1 gene. This alteration results from a C to A substitution at nucleotide position 206, causing the serine (S) at amino acid position 69 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.051

.;T;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D;.

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.90

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.0060

D;D;D

Sift4G

Benign

0.067

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.89

MutPred

0.24

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);

MVP

0.70

MPC

0.54

ClinPred

0.87

GERP RS

5.6

Varity_R

0.17

gMVP

0.50

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over