Genetic Variant PAK5:p.Arg335Gln (chr20-9566371-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_177990.4(PAK5):c.1004G>A(p.Arg335Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000223 in 1,612,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

PAK5
NM_177990.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.17

Publications

25 publications found

Variant links:

Genes affected

PAK5 (HGNC:15916): (p21 (RAC1) activated kinase 5) The protein encoded by this gene is a member of the PAK family of Ser/Thr protein kinases. PAK family members are known to be effectors of Rac/Cdc42 GTPases, which have been implicated in the regulation of cytoskeletal dynamics, proliferation, and cell survival signaling. This kinase contains a CDC42/Rac1 interactive binding (CRIB) motif, and has been shown to bind CDC42 in the presence of GTP. This kinase is predominantly expressed in brain. It is capable of promoting neurite outgrowth, and thus may play a role in neurite development. This kinase is associated with microtubule networks and induces microtubule stabilization. The subcellular localization of this kinase is tightly regulated during cell cycle progression. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

PAK5 links:

ENSG00000286740 (HGNC:):

ENSG00000286740 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010613769).

BS2

High AC in GnomAd4 at 77 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK5	NM_177990.4 link	c.1004G>A	p.Arg335Gln	missense_variant	Exon 5 of 10	ENST00000353224.10	NP_817127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PAK5	ENST00000353224.10 link	c.1004G>A	p.Arg335Gln	missense_variant	Exon 5 of 10	1	NM_177990.4	ENSP00000322957.5
PAK5	ENST00000378423.5 link	c.1004G>A	p.Arg335Gln	missense_variant	Exon 6 of 11	1		ENSP00000367679.1
PAK5	ENST00000378429.3 link	c.1004G>A	p.Arg335Gln	missense_variant	Exon 6 of 11	1		ENSP00000367686.3
ENSG00000286740	ENST00000657954.2 link	n.161+3270C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.000507

AC:

AN:

151880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00690

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000455

AC:

114

AN:

250292

AF XY:

0.000458

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00486

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000193

AC:

282

AN:

1460784

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

134

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00468

AC:

247

AN:

52800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111638

Other (OTH)

AF:

0.000132

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000507

AC:

AN:

151880

Hom.:

Cov.:

AF XY:

0.000809

AC XY:

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41328

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00690

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.0000299

Hom.:

488

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T;T

Eigen

Benign

-0.072

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

.;.;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.67

PhyloP100

7.2

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.17

N;N;N

REVEL

Benign

0.069

Sift

Benign

0.044

D;D;D

Sift4G

Benign

0.47

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.68

MVP

0.28

MPC

0.32

ClinPred

0.13

GERP RS

5.0

Varity_R

0.14

gMVP

0.25

Mutation Taster

=64/36

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over