20-9566236-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_177990.4(PAK5):c.1139C>G(p.Ala380Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PAK5 NM_177990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.40

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05965954).
• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK5	NM_177990.4	c.1139C>G	p.Ala380Gly	missense_variant	5/10	ENST00000353224.10
LOC105372523	XR_937250.3	n.161+3135G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK5	ENST00000353224.10	c.1139C>G	p.Ala380Gly	missense_variant	5/10	1	NM_177990.4	P1
PAK5	ENST00000378423.5	c.1139C>G	p.Ala380Gly	missense_variant	6/11	1		P1
PAK5	ENST00000378429.3	c.1139C>G	p.Ala380Gly	missense_variant	6/11	1		P1
	ENST00000657954.1	n.161+3135G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251244 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461668 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000412 AC: 5

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

Sep 26, 2023

The c.1139C>G (p.A380G) alteration is located in exon 6 (coding exon 3) of the PAK7 gene. This alteration results from a C to G substitution at nucleotide position 1139, causing the alanine (A) at amino acid position 380 to be replaced by a glycine (G). 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	Benign	0.085
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;T
Eigen	Benign	0.031
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.080
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.083	B;B;B
Vest4		0.33
MutPred		0.097		Gain of glycosylation at K379 (P = 0.1051);Gain of glycosylation at K379 (P = 0.1051);Gain of glycosylation at K379 (P = 0.1051);
MVP		0.043
MPC		0.33
ClinPred		0.10	T
GERP RS		5.9
Varity_R		0.11
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs762365457; hg19: chr20-9546883;