20-9580287-C-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_177990.4(PAK5):c.848G>T(p.Arg283Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )
Consequence
PAK5
NM_177990.4 missense
NM_177990.4 missense
Scores
2
6
9
Clinical Significance
Conservation
PhyloP100: 7.53
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAd4 at 18 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAK5 | NM_177990.4 | c.848G>T | p.Arg283Leu | missense_variant | 4/10 | ENST00000353224.10 | |
LOC105372523 | XR_937250.3 | n.591+8979C>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAK5 | ENST00000353224.10 | c.848G>T | p.Arg283Leu | missense_variant | 4/10 | 1 | NM_177990.4 | P1 | |
PAK5 | ENST00000378423.5 | c.848G>T | p.Arg283Leu | missense_variant | 5/11 | 1 | P1 | ||
PAK5 | ENST00000378429.3 | c.848G>T | p.Arg283Leu | missense_variant | 5/11 | 1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251424Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135876
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GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.0000756 AC XY: 55AN XY: 727248
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GnomAD4 genome AF: 0.000118 AC: 18AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74296
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2023 | The c.848G>T (p.R283L) alteration is located in exon 5 (coding exon 2) of the PAK7 gene. This alteration results from a G to T substitution at nucleotide position 848, causing the arginine (R) at amino acid position 283 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Benign
T;T;T
Polyphen
D;D;D
Vest4
MVP
MPC
1.1
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at