dbSNP rs2729762: PAK1:c.*620T>C (chr11-77322654-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_002576.5(PAK1):c.*620T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 235,422 control chromosomes in the GnomAD database, including 15,386 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 ( 9645 hom., cov: 32)

Exomes 𝑓: 0.36 ( 5741 hom. )

Consequence

PAK1
NM_002576.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.25

Publications

13 publications found

Variant links:

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

PAK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

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 link	c.*620T>C		3_prime_UTR_variant	Exon 15 of 15	ENST00000356341.8	NP_002567.3	Q13153-1A0A024R5P0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK1	ENST00000356341.8 link	c.*620T>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_002576.5	ENSP00000348696.4		Q13153-1
PAK1	ENST00000530617.5 link	c.*483T>C		3_prime_UTR_variant	Exon 15 of 15	2		ENSP00000433423.1		B3KNX7

Frequencies

GnomAD3 genomes

AF:

0.354

AC:

53665

AN:

151708

Hom.:

9636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.371

Gnomad AMI

AF:

0.304

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.512

Gnomad FIN

AF:

0.283

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.342

Gnomad OTH

AF:

0.352

GnomAD4 exome

AF:

0.360

AC:

30066

AN:

83596

Hom.:

5741

Cov.:

AF XY:

0.361

AC XY:

14917

AN XY:

41282

show subpopulations

African (AFR)

AF:

0.381

AC:

1038

AN:

2726

American (AMR)

AF:

0.316

AC:

1538

AN:

4862

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

1394

AN:

3880

East Asian (EAS)

AF:

0.465

AC:

4569

AN:

9816

South Asian (SAS)

AF:

0.480

AC:

2381

AN:

4956

European-Finnish (FIN)

AF:

0.263

AC:

398

AN:

1514

Middle Eastern (MID)

AF:

0.333

AC:

133

AN:

400

European-Non Finnish (NFE)

AF:

0.332

AC:

16575

AN:

49852

Other (OTH)

AF:

0.365

AC:

2040

AN:

5590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

916

1833

2749

3666

4582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.354

AC:

53709

AN:

151826

Hom.:

9645

Cov.:

AF XY:

0.353

AC XY:

26224

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.371

AC:

15366

AN:

41410

American (AMR)

AF:

0.318

AC:

4855

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

1262

AN:

3470

East Asian (EAS)

AF:

0.481

AC:

2476

AN:

5146

South Asian (SAS)

AF:

0.511

AC:

2450

AN:

4798

European-Finnish (FIN)

AF:

0.283

AC:

2987

AN:

10538

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.342

AC:

23199

AN:

67876

Other (OTH)

AF:

0.355

AC:

747

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1764

3527

5291

7054

8818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

538

1076

1614

2152

2690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.344

Hom.:

2178

Bravo

AF:

0.355

Asia WGS

AF:

0.505

AC:

1754

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

3.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over