rs1237490

Variant names:

• chr11-77334211-C-T
• rs1237490
• NM_002576.5:c.1414-1344G>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.1414-1344G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 151,732 control chromosomes in the GnomAD database, including 18,429 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 0.45 (18429 hom., cov: 30)
• Consequence: PAK1 NM_002576.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.823
• Publications: 3 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK1	NM_002576.5	c.1414-1344G>A		intron_variant	Intron 13 of 14	ENST00000356341.8	NP_002567.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK1	ENST00000356341.8	c.1414-1344G>A		intron_variant	Intron 13 of 14	1	NM_002576.5	ENSP00000348696.4

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68429 AN: 151614 Hom.: 18386 Cov.: 30

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.427

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

GnomAD4 genome AF: 0.452 AC: 68517 AN: 151732 Hom.: 18429 Cov.: 30 AF XY: 0.449 AC XY: 33263 AN XY: 74152

African (AFR) AF: 0.765 AC: 31671 AN: 41392

American (AMR) AF: 0.324 AC: 4936 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3464

East Asian (EAS) AF: 0.312 AC: 1607 AN: 5156

South Asian (SAS) AF: 0.167 AC: 800 AN: 4784

European-Finnish (FIN) AF: 0.408 AC: 4279 AN: 10498

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23017 AN: 67884

Other (OTH) AF: 0.426 AC: 893 AN: 2098

Alfa AF: 0.378 Hom.: 4670

Bravo AF: 0.461

Asia WGS AF: 0.261 AC: 909 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.15
DANN	Benign	0.10
PhyloP100		-0.82
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: rs1237490; hg19: chr11-77045256;