chr3-196820490-G-A
Position:
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
NM_002577.4 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 9.60
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]
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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 |
---|---|---|---|---|---|---|---|
PAK2 | NM_002577.4 | c.1273G>A | p.Asp425Asn | missense_variant | 13/15 | ENST00000327134.7 | |
PAK2 | XM_011512870.3 | c.1273G>A | p.Asp425Asn | missense_variant | 13/15 | ||
PAK2 | XM_047448218.1 | c.1273G>A | p.Asp425Asn | missense_variant | 13/15 | ||
PAK2 | XM_047448219.1 | c.1273G>A | p.Asp425Asn | missense_variant | 13/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAK2 | ENST00000327134.7 | c.1273G>A | p.Asp425Asn | missense_variant | 13/15 | 2 | NM_002577.4 | P1 | |
PAK2 | ENST00000426668.1 | c.502G>A | p.Asp168Asn | missense_variant | 5/6 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 32
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 submitter | research | Advanced Precision Medicine Laboratory, The Jackson Laboratory for Genomic Medicine | Feb 14, 2024 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0292);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.