Genetic Variant PAK5:p.Ser391Ile (chr20-9566203-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_177990.4(PAK5):c.1172G>T(p.Ser391Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,756 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.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PAK5
NM_177990.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.56

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2958081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK5	NM_177990.4 link	c.1172G>T	p.Ser391Ile	missense_variant	Exon 5 of 10	ENST00000353224.10	NP_817127.1	Q9P286B0AZM9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAK5	ENST00000353224.10 link	c.1172G>T	p.Ser391Ile	missense_variant	Exon 5 of 10	1	NM_177990.4	ENSP00000322957.5	Q9P286
PAK5	ENST00000378423.5 link	c.1172G>T	p.Ser391Ile	missense_variant	Exon 6 of 11	1		ENSP00000367679.1	Q9P286
PAK5	ENST00000378429.3 link	c.1172G>T	p.Ser391Ile	missense_variant	Exon 6 of 11	1		ENSP00000367686.3	Q9P286
ENSG00000286740	ENST00000657954.1 link	n.161+3102C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

0.0047

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

.;.;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.022

D;D;D

Sift4G

Benign

0.15

T;T;T

Polyphen

0.88

P;P;P

Vest4

0.47

MutPred

0.21

Loss of glycosylation at S391 (P = 0.0244);Loss of glycosylation at S391 (P = 0.0244);Loss of glycosylation at S391 (P = 0.0244);

MVP

0.043

MPC

0.73

ClinPred

0.97

GERP RS

5.9

Varity_R

0.42

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over