chr3-196820490-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_002577.4(PAK2):​c.1273G>A​(p.Asp425Asn) 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PAK2
NM_002577.4 missense

Scores

9
8
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.60
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 3-196820490-G-A is Pathogenic according to our data. Variant chr3-196820490-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2921281.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAK2NM_002577.4 linkuse as main transcriptc.1273G>A p.Asp425Asn missense_variant 13/15 ENST00000327134.7
PAK2XM_011512870.3 linkuse as main transcriptc.1273G>A p.Asp425Asn missense_variant 13/15
PAK2XM_047448218.1 linkuse as main transcriptc.1273G>A p.Asp425Asn missense_variant 13/15
PAK2XM_047448219.1 linkuse as main transcriptc.1273G>A p.Asp425Asn missense_variant 13/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAK2ENST00000327134.7 linkuse as main transcriptc.1273G>A p.Asp425Asn missense_variant 13/152 NM_002577.4 P1
PAK2ENST00000426668.1 linkuse as main transcriptc.502G>A p.Asp168Asn missense_variant 5/63

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Knobloch syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchAdvanced Precision Medicine Laboratory, The Jackson Laboratory for Genomic MedicineFeb 14, 2024The c.1273G>A in PAK2 has not been previously reported to our knowledge. The c.1273G>A variant arose de novo; parentage was confirmed (PS2_Strong). The c.1273G>A variant was not observed in the gnomAD database, consistent with the expected frequency of a pathogenic variant in Knobloch syndrome 2 (PM2_Moderate). Multiple lines of computational evidence support a deleterious effect of the c.1273G>A variant on the PAK2 gene or gene product (PP3_Supporting). In summary, evidence suggests that the c.1273G>A in PAK2 is likely pathogenic for Knobloch syndrome 2. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.035
T
BayesDel_noAF
Benign
-0.19
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.46
T
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D
M_CAP
Uncertain
0.087
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.37
D
MutationAssessor
Pathogenic
4.8
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-4.8
D
REVEL
Uncertain
0.48
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.017
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.94
Gain of MoRF binding (P = 0.0292);
MVP
0.81
MPC
3.0
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.66
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-196547361; API