Variant 20-9580167-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_177990.4(PAK5):c.968A>G(p.Glu323Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000773 in 1,612,806 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 3 hom. )

Consequence

PAK5
NM_177990.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.37

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:

LOC105372523 (HGNC:):

LOC105372523 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.305062).

BS2

High AC in GnomAd4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK5	NM_177990.4 linkuse as main transcript	c.968A>G	p.Glu323Gly	missense_variant	4/10	ENST00000353224.10
LOC105372523	XR_937250.3 linkuse as main transcript	n.591+8859T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PAK5	ENST00000353224.10 linkuse as main transcript	c.968A>G	p.Glu323Gly	missense_variant	4/10	1	NM_177990.4	P1
PAK5	ENST00000378423.5 linkuse as main transcript	c.968A>G	p.Glu323Gly	missense_variant	5/11	1		P1
PAK5	ENST00000378429.3 linkuse as main transcript	c.968A>G	p.Glu323Gly	missense_variant	5/11	1		P1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000512

AC:

128

AN:

250172

Hom.:

AF XY:

0.000562

AC XY:

AN XY:

135144

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000804

AC:

1174

AN:

1460514

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

546

AN XY:

726400

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000981

Gnomad4 OTH exome

AF:

0.000912

GnomAD4 genome

AF:

0.000479

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000864

Hom.:

Bravo

AF:

0.000529

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000494

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.968A>G (p.E323G) alteration is located in exon 5 (coding exon 2) of the PAK7 gene. This alteration results from a A to G substitution at nucleotide position 968, causing the glutamic acid (E) at amino acid position 323 to be replaced by a glycine (G). 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

0.33

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

.;.;T

M_CAP

Benign

0.078

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.36

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.84

N;N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.0020

D;D;D

Sift4G

Benign

0.26

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.72

MVP

0.16

MPC

1.0

ClinPred

0.061

GERP RS

5.9

Varity_R

0.29

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over