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GeneBe

20-9566376-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_177990.4(PAK5):c.999C>T(p.Tyr333=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,612,518 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 Benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00031 ( 3 hom. )

Consequence

PAK5
NM_177990.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.72
Variant links:
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 Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 20-9566376-G-A is Benign according to our data. Variant chr20-9566376-G-A is described in ClinVar as [Benign]. Clinvar id is 769076.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.72 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 235 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAK5NM_177990.4 linkuse as main transcriptc.999C>T p.Tyr333= synonymous_variant 5/10 ENST00000353224.10
LOC105372523XR_937250.3 linkuse as main transcriptn.161+3275G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAK5ENST00000353224.10 linkuse as main transcriptc.999C>T p.Tyr333= synonymous_variant 5/101 NM_177990.4 P1
PAK5ENST00000378423.5 linkuse as main transcriptc.999C>T p.Tyr333= synonymous_variant 6/111 P1
PAK5ENST00000378429.3 linkuse as main transcriptc.999C>T p.Tyr333= synonymous_variant 6/111 P1
ENST00000657954.1 linkuse as main transcriptn.161+3275G>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00154
AC:
235
AN:
152110
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00512
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000220
Gnomad OTH
AF:
0.000959
GnomAD3 exomes
AF:
0.000516
AC:
129
AN:
249852
Hom.:
1
AF XY:
0.000378
AC XY:
51
AN XY:
135012
show subpopulations
Gnomad AFR exome
AF:
0.00529
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.000100
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000982
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000274
Gnomad OTH exome
AF:
0.000491
GnomAD4 exome
AF:
0.000311
AC:
454
AN:
1460290
Hom.:
3
Cov.:
32
AF XY:
0.000278
AC XY:
202
AN XY:
726394
show subpopulations
Gnomad4 AFR exome
AF:
0.00595
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000190
Gnomad4 NFE exome
AF:
0.000177
Gnomad4 OTH exome
AF:
0.000563
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00153
AC:
233
AN:
152228
Hom.:
0
Cov.:
31
AF XY:
0.00136
AC XY:
101
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00506
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.000949
Alfa
AF:
0.000888
Hom.:
0
Bravo
AF:
0.00184
EpiCase
AF:
0.000164
EpiControl
AF:
0.000534

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 31, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
Cadd
Benign
0.15
Dann
Benign
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61729218; hg19: chr20-9547023; COSMIC: COSV62023189; API