rs2729747

Variant names:

• chr11-77387434-A-G
• rs2729747
• NM_002576.5:c.190+4897T>C

Variant summary

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

The NM_002576.5(PAK1):​c.190+4897T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 152,062 control chromosomes in the GnomAD database, including 9,726 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 0.35 (9726 hom., cov: 32)
• Consequence: PAK1 NM_002576.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.592
• Publications: 6 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK1	NM_002576.5	c.190+4897T>C		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.190+4897T>C		intron_variant	Intron 2 of 14	1	NM_002576.5	ENSP00000348696.4

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53816 AN: 151942 Hom.: 9712 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.351

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

GnomAD4 genome AF: 0.354 AC: 53865 AN: 152062 Hom.: 9726 Cov.: 32 AF XY: 0.354 AC XY: 26351 AN XY: 74340

African (AFR) AF: 0.373 AC: 15450 AN: 41476

American (AMR) AF: 0.316 AC: 4828 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1259 AN: 3468

East Asian (EAS) AF: 0.478 AC: 2464 AN: 5152

South Asian (SAS) AF: 0.511 AC: 2464 AN: 4820

European-Finnish (FIN) AF: 0.286 AC: 3023 AN: 10570

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23266 AN: 67986

Other (OTH) AF: 0.354 AC: 748 AN: 2112

Alfa AF: 0.346 Hom.: 4858

Bravo AF: 0.354

Asia WGS AF: 0.500 AC: 1738 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.0
DANN	Benign	0.61
PhyloP100		0.59
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: rs2729747; hg19: chr11-77098479; COSMIC: COSV53702272; COSMIC: COSV53702272;