rs2729762

Positions:

• chr11-77322654-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002576.5(PAK1):​c.*620T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 235,422 control chromosomes in the GnomAD database, including 15,386 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 0.35 (9645 hom., cov: 32)
  • Exomes 𝑓: 0.36 (5741 hom.)
• Consequence: PAK1 NM_002576.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK1	NM_002576.5	c.*620T>C		3_prime_UTR_variant	15/15	ENST00000356341.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK1	ENST00000356341.8	c.*620T>C		3_prime_UTR_variant	15/15	1	NM_002576.5	P1
PAK1	ENST00000530617.5	c.*483T>C		3_prime_UTR_variant	15/15	2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53665 AN: 151708 Hom.: 9636 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.352

GnomAD4 exome AF: 0.360 AC: 30066 AN: 83596 Hom.: 5741 Cov.: 0 AF XY: 0.361 AC XY: 14917 AN XY: 41282

Gnomad4 AFR exome AF: 0.381

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.359

Gnomad4 EAS exome AF: 0.465

Gnomad4 SAS exome AF: 0.480

Gnomad4 FIN exome AF: 0.263

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.365

GnomAD4 genome AF: 0.354 AC: 53709 AN: 151826 Hom.: 9645 Cov.: 32 AF XY: 0.353 AC XY: 26224 AN XY: 74190

Gnomad4 AFR AF: 0.371

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.481

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.355

Alfa AF: 0.344 Hom.: 2178

Bravo AF: 0.355

Asia WGS AF: 0.505 AC: 1754 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.84

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: rs2729762; hg19: chr11-77033699; COSMIC: COSV53698934; COSMIC: COSV53698934;