1-88760261-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006256.4(PKN2):c.389G>T(p.Arg130Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,980 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: 31)
• Consequence: PKN2 NM_006256.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22563812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKN2	NM_006256.4	c.389G>T	p.Arg130Leu	missense_variant	3/22	ENST00000370521.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKN2	ENST00000370521.8	c.389G>T	p.Arg130Leu	missense_variant	3/22	1	NM_006256.4	P1
PKN2	ENST00000370513.9	c.389G>T	p.Arg130Leu	missense_variant	3/21	1
PKN2	ENST00000316005.11	c.389G>T	p.Arg130Leu	missense_variant	3/11	5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151980 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 24

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151980 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74238

Gnomad4 AFR AF: 0.00

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: 0.0000147

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 14, 2023

The c.389G>T (p.R130L) alteration is located in exon 3 (coding exon 3) of the PKN2 gene. This alteration results from a G to T substitution at nucleotide position 389, causing the arginine (R) at amino acid position 130 to be replaced by a leucine (L). 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	0.10
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0097	T;T;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.39	B;B;.
Vest4		0.44
MutPred		0.26		Loss of methylation at R130 (P = 0.0504);Loss of methylation at R130 (P = 0.0504);Loss of methylation at R130 (P = 0.0504);
MVP		0.57
MPC		0.62
ClinPred		0.89	D
GERP RS		4.7
Varity_R		0.15
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs749956821; hg19: chr1-89225944;