20-9566230-A-T

Variant names:

• chr20-9566230-A-T
• NM_177990.4:c.1145T>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_177990.4(PAK5):​c.1145T>A​(p.Leu382*) variant causes a stop gained 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. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAK5 NM_177990.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK5	NM_177990.4	c.1145T>A	p.Leu382*	stop_gained	Exon 5 of 10	ENST00000353224.10	NP_817127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK5	ENST00000353224.10	c.1145T>A	p.Leu382*	stop_gained	Exon 5 of 10	1	NM_177990.4	ENSP00000322957.5
PAK5	ENST00000378423.5	c.1145T>A	p.Leu382*	stop_gained	Exon 6 of 11	1		ENSP00000367679.1
PAK5	ENST00000378429.3	c.1145T>A	p.Leu382*	stop_gained	Exon 6 of 11	1		ENSP00000367686.3
ENSG00000286740	ENST00000657954.1	n.161+3129A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Benign	0.74	D
Vest4		0.87
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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.

Other links and lift over

hg19: chr20-9546877;