rs1377470

Variant names:

• chr11-77339669-A-C
• rs1377470
• NM_002576.5:c.1116+977T>G

Variant summary

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

The NM_002576.5(PAK1):​c.1116+977T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 151,908 control chromosomes in the GnomAD database, including 7,657 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 0.31 (7657 hom., cov: 31)
• Consequence: PAK1 NM_002576.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.764
• Publications: 12 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK1	NM_002576.5	c.1116+977T>G		intron_variant	Intron 11 of 14	ENST00000356341.8	NP_002567.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK1	ENST00000356341.8	c.1116+977T>G		intron_variant	Intron 11 of 14	1	NM_002576.5	ENSP00000348696.4

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47647 AN: 151788 Hom.: 7657 Cov.: 31

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.313

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

GnomAD4 genome AF: 0.314 AC: 47661 AN: 151908 Hom.: 7657 Cov.: 31 AF XY: 0.310 AC XY: 23034 AN XY: 74256

African (AFR) AF: 0.309 AC: 12804 AN: 41454

American (AMR) AF: 0.246 AC: 3751 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1188 AN: 3466

East Asian (EAS) AF: 0.219 AC: 1129 AN: 5156

South Asian (SAS) AF: 0.455 AC: 2187 AN: 4806

European-Finnish (FIN) AF: 0.269 AC: 2836 AN: 10560

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22743 AN: 67888

Other (OTH) AF: 0.313 AC: 662 AN: 2114

Alfa AF: 0.326 Hom.: 12402

Bravo AF: 0.308

Asia WGS AF: 0.355 AC: 1236 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		0.76
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: rs1377470; hg19: chr11-77050714;