19-14433525-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_002741.5(PKN1):c.4G>A(p.Ala2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000949 in 1,053,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 9.5e-7 (0 hom.)
• Consequence: PKN1 NM_002741.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

Genes affected

PKN1 (HGNC:9405): (protein kinase N1) The protein encoded by this gene belongs to the protein kinase C superfamily. This kinase is activated by Rho family of small G proteins and may mediate the Rho-dependent signaling pathway. This kinase can be activated by phospholipids and by limited proteolysis. The 3-phosphoinositide dependent protein kinase-1 (PDPK1/PDK1) is reported to phosphorylate this kinase, which may mediate insulin signals to the actin cytoskeleton. The proteolytic activation of this kinase by caspase-3 or related proteases during apoptosis suggests its role in signal transduction related to apoptosis. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity PKN1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31682727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKN1	NM_002741.5	c.4G>A	p.Ala2Thr	missense_variant	1/22	ENST00000242783.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKN1	ENST00000242783.11	c.4G>A	p.Ala2Thr	missense_variant	1/22	1	NM_002741.5	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.49e-7 AC: 1 AN: 1053760 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 497204

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: 0.00

Gnomad4 OTH exome AF: 0.0000240

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2023

The c.4G>A (p.A2T) alteration is located in exon 1 (coding exon 1) of the PKN1 gene. This alteration results from a G to A substitution at nucleotide position 4, causing the alanine (A) at amino acid position 2 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.97	N
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.31	T
Polyphen		0.75	P
Vest4		0.26
MutPred		0.081		Gain of glycosylation at A2 (P = 0.0225);
MVP		0.51
ClinPred		0.56	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31

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: rs1335700690; hg19: chr19-14544337;