11-77336274-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_002576.5(PAK1):c.1225G>A(p.Gly409Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAK1 NM_002576.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

PAK1 (HGNC:8590): (p21 (RAC1) activated kinase 1) This gene encodes a family member of serine/threonine p21-activating kinases, known as PAK proteins. These proteins are critical effectors that link RhoGTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. This specific family member regulates cell motility and morphology. Mutations in this gene have been associated with macrocephaly, seizures, and speech delay. Overexpression of this gene is also reported in many cancer types, and particularly in breast cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Protein kinase (size 251) in uniprot entity PAK1_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_002576.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PAK1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK1	NM_002576.5	c.1225G>A	p.Gly409Arg	missense_variant	13/15	ENST00000356341.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK1	ENST00000356341.8	c.1225G>A	p.Gly409Arg	missense_variant	13/15	1	NM_002576.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.1225G>A (p.G409R) alteration is located in exon 13 (coding exon 12) of the PAK1 gene. This alteration results from a G to A substitution at nucleotide position 1225, causing the glycine (G) at amino acid position 409 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The p.G409 amino acid is located within the activation loop in the kinase catalytic core (Lei, 2000). PAK1 exists as an autoinhibited homodimer until its kinase activity is activated by binding to the GTP-bound forms of Rho GTPases, CDC42 and RAC1 (reviewed in Harms, 2018). The activation loop is bound by the N-terminal kinase inhibitory (KI) segment in the autoinhibited conformation of the PAK1 dimer. Upon binding of the dimer to CDC42 or RAC1, a conformational change releases the activation loop from the KI segment followed by phosphorylation to activate the PAK1 kinase enzyme (Lei, 2000). This alteration is predicted to be deleterious by in silico analysis. 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	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	36
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;T;.;T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.9	H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.6	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.99
MutPred		0.95		Loss of methylation at K404 (P = 0.0645);Loss of methylation at K404 (P = 0.0645);Loss of methylation at K404 (P = 0.0645);.;
MVP		0.87
MPC		2.6
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.91
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -15

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

Publications

LitVar

Other links and lift over

dbSNP: rs1942667410; hg19: chr11-77047319;