rs754468025

Variant names:

• chr20-9566030-A-C
• rs754468025
• NM_177990.4:c.1345T>G

Your query was ambiguous. Multiple possible variants found:

• chr20-9566030-A-C
• chr20-9566030-A-G
• chr20-9566030-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_177990.4(PAK5):​c.1345T>G​(p.Leu449Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. L449M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAK5 NM_177990.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

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.1345T>G	p.Leu449Val	missense	Exon 5 of 10	NP_817127.1	Q9P286
	PAK5	NM_020341.5		c.1345T>G	p.Leu449Val	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.1345T>G	p.Leu449Val	missense	Exon 5 of 10	ENSP00000322957.5	Q9P286
	PAK5	ENST00000378423.5	TSL:1	c.1345T>G	p.Leu449Val	missense	Exon 6 of 11	ENSP00000367679.1	Q9P286
	PAK5	ENST00000378429.3	TSL:1	c.1345T>G	p.Leu449Val	missense	Exon 6 of 11	ENSP00000367686.3	Q9P286

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.076
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.39	T
PhyloP100		1.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.77		Gain of methylation at K454 (P = 0.1396)
MVP		0.41
MPC		0.95
ClinPred		0.96	D
GERP RS		0.79
Varity_R		0.93
gMVP		0.52
Mutation Taster		=73/27	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: rs754468025; hg19: chr20-9546677;