20-9580150-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177990.4(PAK5):c.985C>A(p.Pro329Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAK5 NM_177990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.46

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2565893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK5	NM_177990.4	c.985C>A	p.Pro329Thr	missense_variant	4/10	ENST00000353224.10
LOC105372523	XR_937250.3	n.591+8842G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK5	ENST00000353224.10	c.985C>A	p.Pro329Thr	missense_variant	4/10	1	NM_177990.4	P1
PAK5	ENST00000378423.5	c.985C>A	p.Pro329Thr	missense_variant	5/11	1		P1
PAK5	ENST00000378429.3	c.985C>A	p.Pro329Thr	missense_variant	5/11	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Apr 06, 2022

The c.985C>A (p.P329T) alteration is located in exon 5 (coding exon 2) of the PAK7 gene. This alteration results from a C to A substitution at nucleotide position 985, causing the proline (P) at amino acid position 329 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Benign	-0.0076	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	0.023
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.78	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.059	T;T;T
Sift4G	Uncertain	0.033	D;D;D
Polyphen		0.16	B;B;B
Vest4		0.53
MutPred		0.30		Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);
MVP		0.093
MPC		0.34
ClinPred		0.58	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.16

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: chr20-9560797;