11-77443594-C-T

Variant names:

• chr11-77443594-C-T
• rs527589
• NM_002576.5:c.-22+29958G>A

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+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
• Publications: 10 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 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+29958G>A		intron	N/A	NP_002567.3
	PAK1	NM_001128620.2		c.-22+29958G>A		intron	N/A	NP_001122092.1	Q13153-2
	PAK1	NM_001376268.1		c.-19+29958G>A		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+29958G>A		intron	N/A	ENSP00000348696.4	Q13153-1
	PAK1	ENST00000278568.8	TSL:2	c.-22+29958G>A		intron	N/A	ENSP00000278568.4	Q13153-2
	PAK1	ENST00000873292.1		c.-19+29958G>A		intron	N/A	ENSP00000543351.1

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

African (AFR) AF: 0.982 AC: 40807 AN: 41552

American (AMR) AF: 0.845 AC: 12933 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.923 AC: 3204 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5177 AN: 5192

South Asian (SAS) AF: 0.928 AC: 4484 AN: 4830

European-Finnish (FIN) AF: 0.854 AC: 9043 AN: 10592

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.910 AC: 61899 AN: 68030

Other (OTH) AF: 0.928 AC: 1964 AN: 2116

Alfa AF: 0.916 Hom.: 134228

Bravo AF: 0.926

Asia WGS AF: 0.968 AC: 3366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.15
DANN	Benign	0.75
PhyloP100		-2.6
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: rs527589; hg19: chr11-77154639;