20-9544431-A-G

Variant names:

• chr20-9544431-A-G
• rs75316826
• NM_177990.4:c.1807T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_177990.4(PAK5):​c.1807T>C​(p.Leu603Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,890 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (18 hom.)
• Consequence: PAK5 NM_177990.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.16
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 20-9544431-A-G is Benign according to our data. Variant chr20-9544431-A-G is described in ClinVar as Benign. ClinVar VariationId is 786363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00809 (1233/152338) while in subpopulation AFR AF = 0.027 (1124/41568). AF 95% confidence interval is 0.0257. There are 13 homozygotes in GnomAd4. There are 604 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1233 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177990.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK5	NM_177990.4	MANE Select	c.1807T>C	p.Leu603Leu	synonymous	Exon 8 of 10	NP_817127.1	Q9P286
	PAK5	NM_020341.5		c.1807T>C	p.Leu603Leu	synonymous	Exon 9 of 11	NP_065074.1	Q9P286

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK5	ENST00000353224.10	TSL:1 MANE Select	c.1807T>C	p.Leu603Leu	synonymous	Exon 8 of 10	ENSP00000322957.5	Q9P286
	PAK5	ENST00000378423.5	TSL:1	c.1807T>C	p.Leu603Leu	synonymous	Exon 9 of 11	ENSP00000367679.1	Q9P286
	PAK5	ENST00000378429.3	TSL:1	c.1807T>C	p.Leu603Leu	synonymous	Exon 9 of 11	ENSP00000367686.3	Q9P286

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1229 AN: 152220 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00207 AC: 521 AN: 251460 AF XY: 0.00154

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000898 AC: 1312 AN: 1461552 Hom.: 18 Cov.: 30 AF XY: 0.000780 AC XY: 567 AN XY: 727130

African (AFR) AF: 0.0264 AC: 884 AN: 33470

American (AMR) AF: 0.00203 AC: 91 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000152 AC: 169 AN: 1111700

Other (OTH) AF: 0.00234 AC: 141 AN: 60382

GnomAD4 genome AF: 0.00809 AC: 1233 AN: 152338 Hom.: 13 Cov.: 32 AF XY: 0.00811 AC XY: 604 AN XY: 74498

African (AFR) AF: 0.0270 AC: 1124 AN: 41568

American (AMR) AF: 0.00484 AC: 74 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68028

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00353 Hom.: 2

Bravo AF: 0.00954

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.0
DANN	Benign	0.63
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs75316826; hg19: chr20-9525078;