chr11-77384758-C-T

Variant names:

• chr11-77384758-C-T
• rs568309
• NM_002576.5:c.191-4764G>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.191-4764G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 152,016 control chromosomes in the GnomAD database, including 37,557 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 0.70 (37557 hom., cov: 31)
• Consequence: PAK1 NM_002576.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.157
• Publications: 5 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK1	NM_002576.5	c.191-4764G>A		intron_variant	Intron 2 of 14	ENST00000356341.8	NP_002567.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK1	ENST00000356341.8	c.191-4764G>A		intron_variant	Intron 2 of 14	1	NM_002576.5	ENSP00000348696.4

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105686 AN: 151898 Hom.: 37522 Cov.: 31

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.676

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.682

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

GnomAD4 genome AF: 0.696 AC: 105771 AN: 152016 Hom.: 37557 Cov.: 31 AF XY: 0.692 AC XY: 51396 AN XY: 74320

African (AFR) AF: 0.835 AC: 34647 AN: 41478

American (AMR) AF: 0.547 AC: 8355 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2161 AN: 3472

East Asian (EAS) AF: 0.531 AC: 2744 AN: 5168

South Asian (SAS) AF: 0.621 AC: 2991 AN: 4814

European-Finnish (FIN) AF: 0.676 AC: 7134 AN: 10560

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.672 AC: 45638 AN: 67960

Other (OTH) AF: 0.682 AC: 1433 AN: 2102

Alfa AF: 0.660 Hom.: 14568

Bravo AF: 0.689

Asia WGS AF: 0.605 AC: 2107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.8
DANN	Benign	0.61
PhyloP100		-0.16
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: rs568309; hg19: chr11-77095803; COSMIC: COSV53700691;