11-77364514-G-T

Variant names:

• chr11-77364514-G-T
• rs478134
• NM_002576.5:c.478-5497C>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.478-5497C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 152,112 control chromosomes in the GnomAD database, including 38,165 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 (38165 hom., cov: 32)
• Consequence: PAK1 NM_002576.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.926
• Publications: 4 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK1	NM_002576.5	c.478-5497C>A		intron_variant	Intron 5 of 14	ENST00000356341.8	NP_002567.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK1	ENST00000356341.8	c.478-5497C>A		intron_variant	Intron 5 of 14	1	NM_002576.5	ENSP00000348696.4

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106458 AN: 151994 Hom.: 38129 Cov.: 32

Gnomad AFR AF: 0.850

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.686

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

GnomAD4 genome AF: 0.700 AC: 106543 AN: 152112 Hom.: 38165 Cov.: 32 AF XY: 0.697 AC XY: 51796 AN XY: 74364

African (AFR) AF: 0.850 AC: 35283 AN: 41506

American (AMR) AF: 0.549 AC: 8392 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2157 AN: 3468

East Asian (EAS) AF: 0.549 AC: 2832 AN: 5160

South Asian (SAS) AF: 0.621 AC: 2997 AN: 4826

European-Finnish (FIN) AF: 0.674 AC: 7124 AN: 10568

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

European-Non Finnish (NFE) AF: 0.671 AC: 45637 AN: 67984

Other (OTH) AF: 0.686 AC: 1451 AN: 2114

Alfa AF: 0.704 Hom.: 5690

Bravo AF: 0.695

Asia WGS AF: 0.605 AC: 2106 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.0
DANN	Benign	0.28
PhyloP100		-0.93
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: rs478134; hg19: chr11-77075559;