1-88771466-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006256.4(PKN2):c.668G>A(p.Arg223Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PKN2 NM_006256.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.41

Genes affected

PKN2 (HGNC:9406): (protein kinase N2) Enables RNA polymerase binding activity; histone deacetylase binding activity; and protein serine/threonine kinase activity. Involved in several processes, including apical junction assembly; positive regulation of cell cycle; and positive regulation of viral genome replication. Located in several cellular components, including cleavage furrow; cytoskeleton; and midbody. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33920705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKN2	NM_006256.4	c.668G>A	p.Arg223Lys	missense_variant	5/22	ENST00000370521.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKN2	ENST00000370521.8	c.668G>A	p.Arg223Lys	missense_variant	5/22	1	NM_006256.4	P1
PKN2	ENST00000370513.9	c.668G>A	p.Arg223Lys	missense_variant	5/21	1
PKN2	ENST00000316005.11	c.668G>A	p.Arg223Lys	missense_variant	5/11	5
PKN2	ENST00000436111.1	c.14G>A	p.Arg5Lys	missense_variant	1/5	3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74244

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Mar 06, 2023

The c.668G>A (p.R223K) alteration is located in exon 5 (coding exon 5) of the PKN2 gene. This alteration results from a G to A substitution at nucleotide position 668, causing the arginine (R) at amino acid position 223 to be replaced by a lysine (K). 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	0.22
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.7	D;N;N
REVEL	Benign	0.23
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.32
MutPred		0.72		Gain of ubiquitination at R223 (P = 0.0238);Gain of ubiquitination at R223 (P = 0.0238);Gain of ubiquitination at R223 (P = 0.0238);
MVP		0.45
MPC		0.44
ClinPred		0.91	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1669892191; hg19: chr1-89237149;