19-14446507-C-T

Variant summary

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

The NM_002741.5(PKN1):​c.556C>T​(p.Arg186Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PKN1
NM_002741.5 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.87
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKN1NM_002741.5 linkc.556C>T p.Arg186Trp missense_variant Exon 4 of 22 ENST00000242783.11 NP_002732.3 Q16512-1
PKN1NM_213560.3 linkc.574C>T p.Arg192Trp missense_variant Exon 4 of 22 NP_998725.1 Q16512-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKN1ENST00000242783.11 linkc.556C>T p.Arg186Trp missense_variant Exon 4 of 22 1 NM_002741.5 ENSP00000242783.7 Q16512-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248568
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135046
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000557
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461328
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
726998
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000353
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152234
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
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
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000567

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.574C>T (p.R192W) alteration is located in exon 4 (coding exon 4) of the PKN1 gene. This alteration results from a C to T substitution at nucleotide position 574, causing the arginine (R) at amino acid position 192 to be replaced by a tryptophan (W). 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
0.53
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.40
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
T;.;T;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Benign
0.056
D
MetaRNN
Uncertain
0.65
D;D;D;D
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.69
N;.;.;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-4.0
D;.;.;D
REVEL
Benign
0.21
Sift
Uncertain
0.0010
D;.;.;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
D;.;.;D
Vest4
0.41
MutPred
0.63
Loss of disorder (P = 5e-04);.;.;.;
MVP
0.27
MPC
1.0
ClinPred
0.95
D
GERP RS
1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.24
gMVP
0.32

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1050352249; hg19: chr19-14557319; API