rs11700112

chr20-9566371-C-Achr20-9566371-C-Gchr20-9566371-C-T

Variant summary

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

The NM_177990.4(PAK5):c.1004G>T(p.Arg335Leu) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAK5 NM_177990.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17

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]

(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	UniProt
PAK5	NM_177990.4	c.1004G>T	p.Arg335Leu	missense_variant	5/10	ENST00000353224.10
LOC105372523	XR_937250.3	n.161+3270C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK5	ENST00000353224.10	c.1004G>T	p.Arg335Leu	missense_variant	5/10	1	NM_177990.4	P1
PAK5	ENST00000378423.5	c.1004G>T	p.Arg335Leu	missense_variant	6/11	1		P1
PAK5	ENST00000378429.3	c.1004G>T	p.Arg335Leu	missense_variant	6/11	1		P1
	ENST00000657954.1	n.161+3270C>A		intron_variant, non_coding_transcript_variant

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
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T
Eigen	Benign	0.013
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.011	D;D;D
Sift4G	Benign	0.19	T;T;T
Polyphen		0.026	B;B;B
Vest4		0.60
MutPred		0.38		Loss of methylation at K330 (P = 0.042);Loss of methylation at K330 (P = 0.042);Loss of methylation at K330 (P = 0.042);
MVP		0.13
MPC		0.37
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.26
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11700112; hg19: chr20-9547018;