rs933464171

Variant names:

• chr19-14441368-C-A
• rs933464171
• NM_002741.5:c.247C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-14441368-C-A
• chr19-14441368-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002741.5(PKN1):​c.247C>A​(p.Arg83Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,357,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: PKN1 NM_002741.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.358
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26243937).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002741.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKN1	NM_002741.5	MANE Select	c.247C>A	p.Arg83Ser	missense	Exon 2 of 22	NP_002732.3
	PKN1	NM_213560.3		c.265C>A	p.Arg89Ser	missense	Exon 2 of 22	NP_998725.1	Q16512-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKN1	ENST00000242783.11	TSL:1 MANE Select	c.247C>A	p.Arg83Ser	missense	Exon 2 of 22	ENSP00000242783.7	Q16512-1
	PKN1	ENST00000900936.1		c.247C>A	p.Arg83Ser	missense	Exon 2 of 23	ENSP00000570995.1
	PKN1	ENST00000342216.8	TSL:2	c.265C>A	p.Arg89Ser	missense	Exon 2 of 22	ENSP00000343325.4	Q16512-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.37e-7 AC: 1 AN: 1357486 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 668510

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000354 AC: 1 AN: 28268

American (AMR) AF: 0.00 AC: 0 AN: 28210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23734

East Asian (EAS) AF: 0.00 AC: 0 AN: 32256

South Asian (SAS) AF: 0.00 AC: 0 AN: 74996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4228

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063224

Other (OTH) AF: 0.00 AC: 0 AN: 56148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.048	N
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.36
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.093
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.96	D
Vest4		0.39
MutPred		0.64		Gain of phosphorylation at R83 (P = 0.0417)
MVP		0.35
MPC		1.0
ClinPred		0.82	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.73
gMVP		0.33
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs933464171; hg19: chr19-14552180;