20-9580167-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_177990.4(PAK5):c.968A>G(p.Glu323Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000773 in 1,612,806 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (3 hom.)
• Consequence: PAK5 NM_177990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37

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]

LOC105372523 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.305062).
• BS2: High AC in GnomAd at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK5	NM_177990.4	c.968A>G	p.Glu323Gly	missense_variant	4/10	ENST00000353224.10
LOC105372523	XR_937250.3	n.591+8859T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK5	ENST00000353224.10	c.968A>G	p.Glu323Gly	missense_variant	4/10	1	NM_177990.4	P1
PAK5	ENST00000378423.5	c.968A>G	p.Glu323Gly	missense_variant	5/11	1		P1
PAK5	ENST00000378429.3	c.968A>G	p.Glu323Gly	missense_variant	5/11	1		P1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000512 AC: 128 AN: 250172 Hom.: 0 AF XY: 0.000562 AC XY: 76 AN XY: 135144

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000804 AC: 1174 AN: 1460514 Hom.: 3 Cov.: 33 AF XY: 0.000752 AC XY: 546 AN XY: 726400

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000981

Gnomad4 OTH exome AF: 0.000912

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74474

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000864 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.000873

EpiControl AF: 0.000771

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

Oct 27, 2022

The c.968A>G (p.E323G) alteration is located in exon 5 (coding exon 2) of the PAK7 gene. This alteration results from a A to G substitution at nucleotide position 968, causing the glutamic acid (E) at amino acid position 323 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	0.33
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.84	N;N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.26	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.72
MVP		0.16
MPC		1.0
ClinPred		0.061	T
GERP RS		5.9
Varity_R		0.29
gMVP		0.50

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: rs140079492; hg19: chr20-9560814;