chr1-201293944-T-A

Position:

• chr1-201293944-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001005337.3(PKP1):​c.205T>A​(p.Ser69Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000687 in 1,456,366 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. 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, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP1	NM_001005337.3	c.205T>A	p.Ser69Thr	missense_variant, splice_region_variant	2/14	ENST00000367324.8	NP_001005337.1
PKP1	NM_000299.4	c.205T>A	p.Ser69Thr	missense_variant, splice_region_variant	2/15		NP_000290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP1	ENST00000367324.8	c.205T>A	p.Ser69Thr	missense_variant, splice_region_variant	2/14	1	NM_001005337.3	ENSP00000356293	P1
PKP1	ENST00000263946.7	c.205T>A	p.Ser69Thr	missense_variant, splice_region_variant	2/15	5		ENSP00000263946
PKP1	ENST00000352845.3	c.205T>A	p.Ser69Thr	missense_variant, splice_region_variant	2/14	5		ENSP00000295597

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456366 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724684

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2023

The c.205T>A (p.S69T) alteration is located in exon 2 (coding exon 2) of the PKP1 gene. This alteration results from a T to A substitution at nucleotide position 205, causing the serine (S) at amino acid position 69 to be replaced by a threonine (T). 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	Benign	0.13
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	.;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T;.
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.062	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.97	D;D;D
Vest4		0.60
MutPred		0.20		Gain of glycosylation at S69 (P = 0.0366);Gain of glycosylation at S69 (P = 0.0366);Gain of glycosylation at S69 (P = 0.0366);
MVP		0.64
MPC		0.45
ClinPred		0.69	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.40

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.

Other links and lift over

hg19: chr1-201263072;