rs595654

Variant names:

• chr11-77421766-A-T
• rs595654
• NM_002576.5:c.-21-29225T>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.-21-29225T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 152,056 control chromosomes in the GnomAD database, including 12,028 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 0.38 (12028 hom., cov: 32)
• Consequence: PAK1 NM_002576.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.364
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK1	NM_002576.5	c.-21-29225T>A		intron_variant	Intron 1 of 14	ENST00000356341.8	NP_002567.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK1	ENST00000356341.8	c.-21-29225T>A		intron_variant	Intron 1 of 14	1	NM_002576.5	ENSP00000348696.4

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58357 AN: 151938 Hom.: 12000 Cov.: 32

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.384 AC: 58428 AN: 152056 Hom.: 12028 Cov.: 32 AF XY: 0.383 AC XY: 28473 AN XY: 74354

African (AFR) AF: 0.532 AC: 22057 AN: 41434

American (AMR) AF: 0.304 AC: 4639 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 994 AN: 3468

East Asian (EAS) AF: 0.309 AC: 1600 AN: 5170

South Asian (SAS) AF: 0.167 AC: 807 AN: 4830

European-Finnish (FIN) AF: 0.406 AC: 4300 AN: 10582

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22924 AN: 67972

Other (OTH) AF: 0.375 AC: 792 AN: 2112

Alfa AF: 0.359 Hom.: 1287

Bravo AF: 0.384

Asia WGS AF: 0.248 AC: 863 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.70
PhyloP100		-0.36
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: rs595654; hg19: chr11-77132811;