rs527589

Positions:

• chr11-77443594-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002576.5(PAK1):​c.-22+29958G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 152,288 control chromosomes in the GnomAD database, including 65,179 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.92 (65179 hom., cov: 31)
• Consequence: PAK1 NM_002576.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.55

Genes affected

PAK1 (HGNC:8590): (p21 (RAC1) activated kinase 1) This gene encodes a family member of serine/threonine p21-activating kinases, known as PAK proteins. These proteins are critical effectors that link RhoGTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. This specific family member regulates cell motility and morphology. Mutations in this gene have been associated with macrocephaly, seizures, and speech delay. Overexpression of this gene is also reported in many cancer types, and particularly in breast cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK1	NM_002576.5	c.-22+29958G>A		intron_variant		ENST00000356341.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK1	ENST00000356341.8	c.-22+29958G>A		intron_variant		1	NM_002576.5	P1

Frequencies

GnomAD3 genomes AF: 0.924 AC: 140574 AN: 152170 Hom.: 65117 Cov.: 31

Gnomad AFR AF: 0.982

Gnomad AMI AF: 0.985

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.923

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.929

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.926

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.924 AC: 140696 AN: 152288 Hom.: 65179 Cov.: 31 AF XY: 0.921 AC XY: 68593 AN XY: 74450

Gnomad4 AFR AF: 0.982

Gnomad4 AMR AF: 0.845

Gnomad4 ASJ AF: 0.923

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.928

Gnomad4 FIN AF: 0.854

Gnomad4 NFE AF: 0.910

Gnomad4 OTH AF: 0.928

Alfa AF: 0.914 Hom.: 83442

Bravo AF: 0.926

Asia WGS AF: 0.968 AC: 3366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.15
DANN	Benign	0.75

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

LitVar

Other links and lift over

dbSNP: rs527589; hg19: chr11-77154639;