20-9562975-C-T

Variant names:

• chr20-9562975-C-T
• rs2297345
• NM_177990.4:c.1532G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177990.4(PAK5):​c.1532G>A​(p.Ser511Asn) variant causes a missense change. The variant allele was found at a frequency of 0.33 in 1,609,848 control chromosomes in the GnomAD database, including 100,081 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.45 (19330 hom., cov: 31)
  • Exomes 𝑓: 0.32 (80751 hom.)
• Consequence: PAK5 NM_177990.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.26
• Publications: 37 publications found

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]

ENSG00000286740 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7013694E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK5	NM_177990.4	c.1532G>A	p.Ser511Asn	missense_variant	Exon 6 of 10	ENST00000353224.10	NP_817127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK5	ENST00000353224.10	c.1532G>A	p.Ser511Asn	missense_variant	Exon 6 of 10	1	NM_177990.4	ENSP00000322957.5
PAK5	ENST00000378423.5	c.1532G>A	p.Ser511Asn	missense_variant	Exon 7 of 11	1		ENSP00000367679.1
PAK5	ENST00000378429.3	c.1532G>A	p.Ser511Asn	missense_variant	Exon 7 of 11	1		ENSP00000367686.3
ENSG00000286740	ENST00000657954.2	n.35C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68724 AN: 151814 Hom.: 19272 Cov.: 31

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.435

GnomAD2 exomes AF: 0.372 AC: 93360 AN: 251240 AF XY: 0.356

Gnomad AFR exome AF: 0.811

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.574

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.317 AC: 462285 AN: 1457916 Hom.: 80751 Cov.: 31 AF XY: 0.316 AC XY: 228925 AN XY: 725420

African (AFR) AF: 0.815 AC: 27185 AN: 33372

American (AMR) AF: 0.405 AC: 18098 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10519 AN: 26100

East Asian (EAS) AF: 0.567 AC: 22508 AN: 39672

South Asian (SAS) AF: 0.293 AC: 25219 AN: 86066

European-Finnish (FIN) AF: 0.289 AC: 15410 AN: 53404

Middle Eastern (MID) AF: 0.353 AC: 2030 AN: 5750

European-Non Finnish (NFE) AF: 0.289 AC: 320176 AN: 1108600

Other (OTH) AF: 0.351 AC: 21140 AN: 60274

GnomAD4 genome AF: 0.453 AC: 68843 AN: 151932 Hom.: 19330 Cov.: 31 AF XY: 0.452 AC XY: 33580 AN XY: 74258

African (AFR) AF: 0.799 AC: 33123 AN: 41476

American (AMR) AF: 0.372 AC: 5664 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1414 AN: 3466

East Asian (EAS) AF: 0.569 AC: 2935 AN: 5160

South Asian (SAS) AF: 0.310 AC: 1485 AN: 4794

European-Finnish (FIN) AF: 0.288 AC: 3035 AN: 10548

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19933 AN: 67938

Other (OTH) AF: 0.439 AC: 928 AN: 2114

Alfa AF: 0.354 Hom.: 31607

Bravo AF: 0.480

TwinsUK AF: 0.284 AC: 1053

ALSPAC AF: 0.284 AC: 1096

ESP6500AA AF: 0.791 AC: 3483

ESP6500EA AF: 0.309 AC: 2654

ExAC AF: 0.376 AC: 45631

Asia WGS AF: 0.473 AC: 1645 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.303

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.32
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	.;.;T
MetaRNN	Benign	0.000017	T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		6.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	2.2	N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.089
MPC		0.26
ClinPred		0.0077	T
GERP RS		5.9
Varity_R		0.42
gMVP		0.38
Mutation Taster		=99/1	polymorphism (auto)

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: rs2297345; hg19: chr20-9543622; COSMIC: COSV62027637;