20-9566327-A-C

Position:

• chr20-9566327-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_177990.4(PAK5):​c.1048T>G​(p.Tyr350Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAK5 NM_177990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAK5	NM_177990.4	c.1048T>G	p.Tyr350Asp	missense_variant	5/10	ENST00000353224.10	NP_817127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAK5	ENST00000353224.10	c.1048T>G	p.Tyr350Asp	missense_variant	5/10	1	NM_177990.4	ENSP00000322957.5
PAK5	ENST00000378423.5	c.1048T>G	p.Tyr350Asp	missense_variant	6/11	1		ENSP00000367679.1
PAK5	ENST00000378429.3	c.1048T>G	p.Tyr350Asp	missense_variant	6/11	1		ENSP00000367686.3
ENSG00000286740	ENST00000657954.1	n.161+3226A>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.1048T>G (p.Y350D) alteration is located in exon 6 (coding exon 3) of the PAK7 gene. This alteration results from a T to G substitution at nucleotide position 1048, causing the tyrosine (Y) at amino acid position 350 to be replaced by an aspartic acid (D). 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	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	.;.;T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.55	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.023	D;D;D
Sift4G	Benign	0.19	T;T;T
Polyphen		0.92	P;P;P
Vest4		0.64
MutPred		0.26		Loss of phosphorylation at Y350 (P = 0.0197);Loss of phosphorylation at Y350 (P = 0.0197);Loss of phosphorylation at Y350 (P = 0.0197);
MVP		0.36
MPC		1.3
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.61

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-9546974;