3-196803142-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_002577.4(PAK2):c.414A>G(p.Lys138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,384,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAK2 NM_002577.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.149

Genes affected

PAK2 (HGNC:8591): (p21 (RAC1) activated kinase 2) The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-196803142-A-G is Benign according to our data. Variant chr3-196803142-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3042971.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.149 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0112 (15449/1384390) while in subpopulation AMR AF= 0.0343 (1155/33662). AF 95% confidence interval is 0.0327. There are 0 homozygotes in gnomad4_exome. There are 10744 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK2	NM_002577.4	c.414A>G	p.Lys138=	synonymous_variant	4/15	ENST00000327134.7
PAK2	XM_011512870.3	c.414A>G	p.Lys138=	synonymous_variant	4/15
PAK2	XM_047448218.1	c.414A>G	p.Lys138=	synonymous_variant	4/15
PAK2	XM_047448219.1	c.414A>G	p.Lys138=	synonymous_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK2	ENST00000327134.7	c.414A>G	p.Lys138=	synonymous_variant	4/15	2	NM_002577.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151992 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0112 AC: 15449 AN: 1384390 Hom.: 0 Cov.: 30 AF XY: 0.0157 AC XY: 10744 AN XY: 683468

Gnomad4 AFR exome AF: 0.00795

Gnomad4 AMR exome AF: 0.0343

Gnomad4 ASJ exome AF: 0.0187

Gnomad4 EAS exome AF: 0.0119

Gnomad4 SAS exome AF: 0.0178

Gnomad4 FIN exome AF: 0.00950

Gnomad4 NFE exome AF: 0.00998

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151992 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74226

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00876 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PAK2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2022

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	2.9
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs73205842; hg19: chr3-196530013; COSMIC: COSV59079253; COSMIC: COSV59079253;