Genetic Variant NM_002741.5:c.67G>A (chr19-14441188-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002741.5(PKN1):c.67G>A(p.Gly23Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000351 in 1,596,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

PKN1
NM_002741.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.48

Publications

2 publications found

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]

PKN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17449093).

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.67G>A	p.Gly23Arg	missense	Exon 2 of 22	NP_002732.3
	PKN1	NM_213560.3		c.85G>A	p.Gly29Arg	missense	Exon 2 of 22	NP_998725.1	Q16512-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKN1	ENST00000242783.11	TSL:1 MANE Select	c.67G>A	p.Gly23Arg	missense	Exon 2 of 22	ENSP00000242783.7	Q16512-1
PKN1	ENST00000900936.1		c.67G>A	p.Gly23Arg	missense	Exon 2 of 23	ENSP00000570995.1
PKN1	ENST00000342216.8	TSL:2	c.85G>A	p.Gly29Arg	missense	Exon 2 of 22	ENSP00000343325.4	Q16512-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000185

AC:

AN:

215906

AF XY:

0.0000167

show subpopulations

Gnomad AFR exome

AF:

0.000170

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000332

AC:

AN:

1444670

Hom.:

Cov.:

AF XY:

0.0000320

AC XY:

AN XY:

718592

show subpopulations

African (AFR)

AF:

0.000374

AC:

AN:

32084

American (AMR)

AF:

0.00

AC:

AN:

41336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25362

East Asian (EAS)

AF:

0.0000516

AC:

AN:

38726

South Asian (SAS)

AF:

0.00

AC:

AN:

84366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0000253

AC:

AN:

1106248

Other (OTH)

AF:

0.000101

AC:

AN:

59642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000849

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000251

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.042

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.077

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

4.5

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.76

REVEL

Benign

0.11

Sift

Benign

0.16

Sift4G

Benign

0.33

Polyphen

0.85

Vest4

0.34

MutPred

0.28

Gain of solvent accessibility (P = 0.0055)

MVP

0.45

MPC

1.1

ClinPred

0.25

GERP RS

4.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.16

gMVP

0.37

Mutation Taster

=77/23

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over