19-14450338-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002741.5(PKN1):c.631G>C(p.Val211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKN1 NM_002741.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.470

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042830884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKN1	NM_002741.5	c.631G>C	p.Val211Leu	missense_variant	5/22	ENST00000242783.11
PKN1	NM_213560.3	c.649G>C	p.Val217Leu	missense_variant	5/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKN1	ENST00000242783.11	c.631G>C	p.Val211Leu	missense_variant	5/22	1	NM_002741.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 26, 2024

The c.649G>C (p.V217L) alteration is located in exon 5 (coding exon 5) of the PKN1 gene. This alteration results from a G to C substitution at nucleotide position 649, causing the valine (V) at amino acid position 217 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	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	14
Dann	Benign	0.71
DEOGEN2	Benign	0.065	T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.17	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.26	N;.;N
REVEL	Benign	0.012
Sift	Benign	0.94	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.27
MutPred		0.24		Gain of disorder (P = 0.1151);.;.;
MVP		0.25
MPC		0.32
ClinPred		0.035	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.051
gMVP		0.076

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-14561150;