1-88760296-C-A

Variant summary

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

The NM_006256.4(PKN2):c.424C>A(p.Gln142Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,411,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000014 (0 hom.)
• Consequence: PKN2 NM_006256.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25

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=0.08827114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKN2	NM_006256.4	c.424C>A	p.Gln142Lys	missense_variant	3/22	ENST00000370521.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKN2	ENST00000370521.8	c.424C>A	p.Gln142Lys	missense_variant	3/22	1	NM_006256.4	P1
PKN2	ENST00000370513.9	c.424C>A	p.Gln142Lys	missense_variant	3/21	1
PKN2	ENST00000316005.11	c.424C>A	p.Gln142Lys	missense_variant	3/11	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246588 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1411906 Hom.: 0 Cov.: 23 AF XY: 0.00000142 AC XY: 1 AN XY: 705520

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: 0.0000375

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Aug 16, 2021

The c.424C>A (p.Q142K) alteration is located in exon 3 (coding exon 3) of the PKN2 gene. This alteration results from a C to A substitution at nucleotide position 424, causing the glutamine (Q) at amino acid position 142 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	0.069
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	16
Dann	Benign	0.63
DEOGEN2	Benign	0.0029	T;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.088	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.059
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.13
MutPred		0.46		Loss of ubiquitination at K139 (P = 0.0167);Loss of ubiquitination at K139 (P = 0.0167);Loss of ubiquitination at K139 (P = 0.0167);
MVP		0.29
MPC		0.54
ClinPred		0.18	T
GERP RS		0.75
Varity_R		0.16
gMVP		0.22

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: rs1421789734; hg19: chr1-89225979;