3-196820490-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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: 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;