11-77467875-A-T

Variant names:

• chr11-77467875-A-T
• rs3015993
• NM_002576.5:c.-22+5677T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000356341.8(PAK1):​c.-22+5677T>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 152,110 control chromosomes in the GnomAD database, including 38,169 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 (38169 hom., cov: 33)
• Consequence: PAK1 ENST00000356341.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.350
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000356341.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK1	NM_002576.5	MANE Select	c.-22+5677T>A		intron	N/A	NP_002567.3
	PAK1	NM_001128620.2		c.-22+5677T>A		intron	N/A	NP_001122092.1
	PAK1	NM_001376268.1		c.-19+5677T>A		intron	N/A	NP_001363197.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK1	ENST00000356341.8	TSL:1 MANE Select	c.-22+5677T>A		intron	N/A	ENSP00000348696.4
	PAK1	ENST00000278568.8	TSL:2	c.-22+5677T>A		intron	N/A	ENSP00000278568.4
	PAK1	ENST00000524847.5	TSL:5	c.-79+5677T>A		intron	N/A	ENSP00000432477.1

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106439 AN: 151994 Hom.: 38134 Cov.: 33

Gnomad AFR AF: 0.850

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.673

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.672

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: 106523 AN: 152110 Hom.: 38169 Cov.: 33 AF XY: 0.696 AC XY: 51742 AN XY: 74368

African (AFR) AF: 0.851 AC: 35310 AN: 41508

American (AMR) AF: 0.550 AC: 8402 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2182 AN: 3470

East Asian (EAS) AF: 0.532 AC: 2751 AN: 5168

South Asian (SAS) AF: 0.613 AC: 2960 AN: 4826

European-Finnish (FIN) AF: 0.673 AC: 7105 AN: 10558

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.672 AC: 45688 AN: 67986

Other (OTH) AF: 0.686 AC: 1449 AN: 2112

Alfa AF: 0.671 Hom.: 4100

Bravo AF: 0.695

Asia WGS AF: 0.603 AC: 2100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.70
PhyloP100		-0.35
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: rs3015993; hg19: chr11-77178920;