rs2154754

Variant names:

• chr11-77467653-G-A
• rs2154754
• NM_002576.5:c.-22+5899C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002576.5(PAK1):​c.-22+5899C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 151,876 control chromosomes in the GnomAD database, including 11,228 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 0.37 (11228 hom., cov: 32)
• Consequence: PAK1 NM_002576.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.454
• Publications: 9 publications found

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]

PAK1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with macrocephaly, seizures, and speech delay

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002576.5. 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
	PAK1	NM_002576.5	MANE Select	c.-22+5899C>T		intron	N/A	NP_002567.3
	PAK1	NM_001128620.2		c.-22+5899C>T		intron	N/A	NP_001122092.1	Q13153-2
	PAK1	NM_001376268.1		c.-19+5899C>T		intron	N/A	NP_001363197.1	Q13153-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK1	ENST00000356341.8	TSL:1 MANE Select	c.-22+5899C>T		intron	N/A	ENSP00000348696.4	Q13153-1
	PAK1	ENST00000278568.8	TSL:2	c.-22+5899C>T		intron	N/A	ENSP00000278568.4	Q13153-2
	PAK1	ENST00000873292.1		c.-19+5899C>T		intron	N/A	ENSP00000543351.1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56033 AN: 151754 Hom.: 11203 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.363

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

GnomAD4 genome AF: 0.369 AC: 56100 AN: 151876 Hom.: 11228 Cov.: 32 AF XY: 0.369 AC XY: 27364 AN XY: 74242

African (AFR) AF: 0.526 AC: 21819 AN: 41466

American (AMR) AF: 0.289 AC: 4412 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 872 AN: 3472

East Asian (EAS) AF: 0.310 AC: 1595 AN: 5142

South Asian (SAS) AF: 0.149 AC: 712 AN: 4776

European-Finnish (FIN) AF: 0.400 AC: 4223 AN: 10552

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21398 AN: 67912

Other (OTH) AF: 0.362 AC: 764 AN: 2110

Alfa AF: 0.330 Hom.: 33496

Bravo AF: 0.368

Asia WGS AF: 0.237 AC: 825 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	9.4
DANN	Benign	0.59
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2154754; hg19: chr11-77178698;