Genetic Variant PAK2:p.Thr402Ile (chr3-196820422-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_002577.4(PAK2):c.1205C>T(p.Thr402Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PAK2
NM_002577.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Publications

0 publications found

Variant links:

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]

PAK2 Gene-Disease associations (from GenCC):

Knobloch syndrome 2
Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

PAK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a mutagenesis_site Abolishes kinase activity and greatly inhibits autophosphorylation of PAK-2p27 and PAK-2p34. (size 0) in uniprot entity PAK2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.4003 (above the threshold of 3.09). Trascript score misZ: 1.8557 (below the threshold of 3.09). GenCC associations: The gene is linked to Knobloch syndrome 2.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002577.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK2	NM_002577.4	MANE Select	c.1205C>T	p.Thr402Ile	missense	Exon 13 of 15	NP_002568.2	Q13177

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAK2	ENST00000327134.7	TSL:2 MANE Select	c.1205C>T	p.Thr402Ile	missense	Exon 13 of 15	ENSP00000314067.3	Q13177
PAK2	ENST00000871388.1		c.1205C>T	p.Thr402Ile	missense	Exon 14 of 16	ENSP00000541447.1
PAK2	ENST00000871391.1		c.1205C>T	p.Thr402Ile	missense	Exon 14 of 16	ENSP00000541450.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.2

PhyloP100

7.6

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.93

MutPred

0.78

Loss of phosphorylation at T402 (P = 0.0082)

MVP

0.82

MPC

3.2

ClinPred

0.99

GERP RS

3.8

Varity_R

0.83

gMVP

0.88

Mutation Taster

=27/73

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over