2-158577156-A-G

Position:

• chr2-158577156-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003628.6(PKP4):​c.133-115A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0327 in 588,318 control chromosomes in the GnomAD database, including 1,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (832 hom., cov: 32)
  • Exomes 𝑓: 0.021 (294 hom.)
• Consequence: PKP4 NM_003628.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.267

Genes affected

PKP4 (HGNC:9026): (plakophilin 4) Armadillo-like proteins are characterized by a series of armadillo repeats, first defined in the Drosophila 'armadillo' gene product, that are typically 42 to 45 amino acids in length. These proteins can be divided into subfamilies based on their number of repeats, their overall sequence similarity, and the dispersion of the repeats throughout their sequences. Members of the p120(ctn)/plakophilin subfamily of Armadillo-like proteins, including CTNND1, CTNND2, PKP1, PKP2, PKP4, and ARVCF. PKP4 may be a component of desmosomal plaque and other adhesion plaques and is thought to be involved in regulating junctional plaque organization and cadherin function. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2015]

PKP4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-158577156-A-G is Benign according to our data. Variant chr2-158577156-A-G is described in ClinVar as [Benign]. Clinvar id is 1296431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP4	NM_003628.6	c.133-115A>G		intron_variant		ENST00000389759.8	NP_003619.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP4	ENST00000389759.8	c.133-115A>G		intron_variant		1	NM_003628.6	ENSP00000374409.3

Frequencies

GnomAD3 genomes AF: 0.0668 AC: 10158 AN: 152096 Hom.: 826 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0452

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0566

GnomAD4 exome AF: 0.0208 AC: 9066 AN: 436102 Hom.: 294 AF XY: 0.0197 AC XY: 4500 AN XY: 228402

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.0283

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00929

Gnomad4 FIN exome AF: 0.00690

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0358

GnomAD4 genome AF: 0.0668 AC: 10173 AN: 152216 Hom.: 832 Cov.: 32 AF XY: 0.0651 AC XY: 4849 AN XY: 74434

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.0452

Gnomad4 ASJ AF: 0.0813

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.00735

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0559

Alfa AF: 0.0597 Hom.: 98

Bravo AF: 0.0767

Asia WGS AF: 0.0180 AC: 65 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.8
DANN	Benign	0.52

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

LitVar

Other links and lift over

dbSNP: rs6712810; hg19: chr2-159433668;