9-128705348-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013355.5(PKN3):c.70C>T(p.Arg24Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000469 in 1,427,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: PKN3 NM_013355.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

Genes affected

PKN3 (HGNC:17999): (protein kinase N3) Predicted to enable protein serine/threonine kinase activity. Involved in epithelial cell migration. Predicted to be located in Golgi apparatus and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKN3	NM_013355.5	c.70C>T	p.Arg24Cys	missense_variant	2/22	ENST00000291906.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKN3	ENST00000291906.5	c.70C>T	p.Arg24Cys	missense_variant	2/22	1	NM_013355.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000361 AC: 7 AN: 193762 Hom.: 0 AF XY: 0.0000474 AC XY: 5 AN XY: 105448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000357

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000155

Gnomad FIN exome AF: 0.0000579

Gnomad NFE exome AF: 0.0000120

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000469 AC: 67 AN: 1427562 Hom.: 0 Cov.: 32 AF XY: 0.0000438 AC XY: 31 AN XY: 707428

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000516

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000686

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.0000200

Gnomad4 NFE exome AF: 0.0000228

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000250 AC: 3

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

Dec 21, 2022

The c.70C>T (p.R24C) alteration is located in exon 2 (coding exon 2) of the PKN3 gene. This alteration results from a C to T substitution at nucleotide position 70, causing the arginine (R) at amino acid position 24 to be replaced by a cysteine (C). 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	0.32
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.62		Loss of MoRF binding (P = 0.0092);
MVP		0.44
MPC		1.1
ClinPred		0.77	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs765945214; hg19: chr9-131467627;