Variant 11-77340638-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002576.5(PAK1):c.1116+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,442,560 control chromosomes in the GnomAD database, including 78,620 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5669 hom., cov: 32)

Exomes 𝑓: 0.33 ( 72951 hom. )

Consequence

PAK1
NM_002576.5 splice_region, intron

Scores

Splicing: ADA: 0.0006125

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.88

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 11-77340638-G-C is Benign according to our data. Variant chr11-77340638-G-C is described in ClinVar as [Benign]. Clinvar id is 1282238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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/exons	MANE	UniProt
PAK1	NM_002576.5 linkuse as main transcript	c.1116+8C>G		splice_region_variant, intron_variant		ENST00000356341.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK1	ENST00000356341.8 linkuse as main transcript	c.1116+8C>G		splice_region_variant, intron_variant		1	NM_002576.5	P1	Q13153-1

Frequencies

GnomAD3 genomes

AF:

0.247

AC:

37480

AN:

152000

Hom.:

5669

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0752

Gnomad AMI

AF:

0.304

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.219

Gnomad SAS

AF:

0.455

Gnomad FIN

AF:

0.269

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.334

Gnomad OTH

AF:

0.256

GnomAD3 exomes

AF:

0.294

AC:

73835

AN:

250914

Hom.:

12293

AF XY:

0.311

AC XY:

42152

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.0698

Gnomad AMR exome

AF:

0.175

Gnomad ASJ exome

AF:

0.336

Gnomad EAS exome

AF:

0.223

Gnomad SAS exome

AF:

0.451

Gnomad FIN exome

AF:

0.281

Gnomad NFE exome

AF:

0.329

Gnomad OTH exome

AF:

0.323

GnomAD4 exome

AF:

0.327

AC:

422375

AN:

1290440

Hom.:

72951

Cov.:

AF XY:

0.332

AC XY:

216574

AN XY:

651432

show subpopulations

Gnomad4 AFR exome

AF:

0.0619

Gnomad4 AMR exome

AF:

0.179

Gnomad4 ASJ exome

AF:

0.339

Gnomad4 EAS exome

AF:

0.216

Gnomad4 SAS exome

AF:

0.445

Gnomad4 FIN exome

AF:

0.280

Gnomad4 NFE exome

AF:

0.339

Gnomad4 OTH exome

AF:

0.324

GnomAD4 genome

AF:

0.246

AC:

37484

AN:

152120

Hom.:

5669

Cov.:

AF XY:

0.245

AC XY:

18238

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0752

Gnomad4 AMR

AF:

0.224

Gnomad4 ASJ

AF:

0.342

Gnomad4 EAS

AF:

0.219

Gnomad4 SAS

AF:

0.455

Gnomad4 FIN

AF:

0.269

Gnomad4 NFE

AF:

0.334

Gnomad4 OTH

AF:

0.258

Alfa

AF:

0.281

Hom.:

2046

Bravo

AF:

0.231

Asia WGS

AF:

0.345

AC:

1201

AN:

3478

EpiCase

AF:

0.332

EpiControl

AF:

0.336

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PAK1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

Cadd

Benign

Dann

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00061

dbscSNV1_RF

Benign

0.0060

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over