20-9566375-C-G

Variant names:

• chr20-9566375-C-G
• rs58486349
• NM_177990.4:c.1000G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_177990.4(PAK5):​c.1000G>C​(p.Asp334His) variant causes a missense change. The variant allele was found at a frequency of 0.000884 in 1,612,668 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D334N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: PAK5 NM_177990.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• Publications: 5 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035069287).
• BS2: High AC in GnomAd4 at 656 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177990.4. 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
	PAK5	NM_177990.4	MANE Select	c.1000G>C	p.Asp334His	missense	Exon 5 of 10	NP_817127.1	Q9P286
	PAK5	NM_020341.5		c.1000G>C	p.Asp334His	missense	Exon 6 of 11	NP_065074.1	Q9P286

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK5	ENST00000353224.10	TSL:1 MANE Select	c.1000G>C	p.Asp334His	missense	Exon 5 of 10	ENSP00000322957.5	Q9P286
	PAK5	ENST00000378423.5	TSL:1	c.1000G>C	p.Asp334His	missense	Exon 6 of 11	ENSP00000367679.1	Q9P286
	PAK5	ENST00000378429.3	TSL:1	c.1000G>C	p.Asp334His	missense	Exon 6 of 11	ENSP00000367686.3	Q9P286

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 657 AN: 152052 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00116 AC: 290 AN: 249992 AF XY: 0.000955

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000527 AC: 769 AN: 1460498 Hom.: 3 Cov.: 32 AF XY: 0.000454 AC XY: 330 AN XY: 726482

African (AFR) AF: 0.0150 AC: 502 AN: 33466

American (AMR) AF: 0.000738 AC: 33 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 12 AN: 26092

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52698

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1111526

Other (OTH) AF: 0.00108 AC: 65 AN: 60368

GnomAD4 genome AF: 0.00431 AC: 656 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.00422 AC XY: 314 AN XY: 74412

African (AFR) AF: 0.0152 AC: 630 AN: 41498

American (AMR) AF: 0.000850 AC: 13 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000363 Hom.: 0

Bravo AF: 0.00486

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.47	T
PhyloP100		7.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.073	T
Polyphen		0.64	P
Vest4		0.47
MVP		0.12
MPC		0.93
ClinPred		0.057	T
GERP RS		5.9
Varity_R		0.27
gMVP		0.32
Mutation Taster		=100/0	polymorphism

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: rs58486349; hg19: chr20-9547022;