rs2844337

Variant names:

• chr11-77322663-A-C
• rs2844337
• NM_002576.5:c.*611T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-77322663-A-C
• chr11-77322663-A-G
• chr11-77322663-A-T

Variant summary

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

The NM_002576.5(PAK1):​c.*611T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 242,172 control chromosomes in the GnomAD database, including 10,942 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 0.29 (6448 hom., cov: 31)
  • Exomes 𝑓: 0.30 (4494 hom.)
• Consequence: PAK1 NM_002576.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204
• Publications: 11 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=-0.48).
• 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.*611T>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000356341.8	NP_002567.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK1	ENST00000356341.8	c.*611T>G		3_prime_UTR_variant	Exon 15 of 15	1	NM_002576.5	ENSP00000348696.4
PAK1	ENST00000530617.5	c.*474T>G		3_prime_UTR_variant	Exon 15 of 15	2		ENSP00000433423.1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43294 AN: 151768 Hom.: 6444 Cov.: 31

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.291

GnomAD4 exome AF: 0.302 AC: 27296 AN: 90286 Hom.: 4494 Cov.: 0 AF XY: 0.306 AC XY: 13698 AN XY: 44782

African (AFR) AF: 0.211 AC: 637 AN: 3022

American (AMR) AF: 0.223 AC: 1115 AN: 4996

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1365 AN: 4110

East Asian (EAS) AF: 0.223 AC: 2311 AN: 10362

South Asian (SAS) AF: 0.412 AC: 2313 AN: 5614

European-Finnish (FIN) AF: 0.245 AC: 435 AN: 1776

Middle Eastern (MID) AF: 0.300 AC: 126 AN: 420

European-Non Finnish (NFE) AF: 0.317 AC: 17095 AN: 54004

Other (OTH) AF: 0.317 AC: 1899 AN: 5982

GnomAD4 genome AF: 0.285 AC: 43320 AN: 151886 Hom.: 6448 Cov.: 31 AF XY: 0.283 AC XY: 21013 AN XY: 74228

African (AFR) AF: 0.209 AC: 8679 AN: 41446

American (AMR) AF: 0.239 AC: 3649 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1185 AN: 3466

East Asian (EAS) AF: 0.234 AC: 1204 AN: 5146

South Asian (SAS) AF: 0.454 AC: 2183 AN: 4804

European-Finnish (FIN) AF: 0.266 AC: 2804 AN: 10542

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.334 AC: 22645 AN: 67888

Other (OTH) AF: 0.291 AC: 615 AN: 2110

Alfa AF: 0.296 Hom.: 8969

Bravo AF: 0.277

Asia WGS AF: 0.360 AC: 1252 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		0.20
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: rs2844337; hg19: chr11-77033708; COSMIC: COSV53698297; COSMIC: COSV53698297;