chr3-196812752-A-C

Position:

• chr3-196812752-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_002577.4(PAK2):​c.836A>C​(p.Gln279Pro) 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: 8.80

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant 3-196812752-A-C is Pathogenic according to our data. Variant chr3-196812752-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3362907.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAK2	NM_002577.4	c.836A>C	p.Gln279Pro	missense_variant	10/15	ENST00000327134.7	NP_002568.2
PAK2	XM_011512870.3	c.836A>C	p.Gln279Pro	missense_variant	10/15		XP_011511172.1
PAK2	XM_047448218.1	c.836A>C	p.Gln279Pro	missense_variant	10/15		XP_047304174.1
PAK2	XM_047448219.1	c.836A>C	p.Gln279Pro	missense_variant	10/15		XP_047304175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAK2	ENST00000327134.7	c.836A>C	p.Gln279Pro	missense_variant	10/15	2	NM_002577.4	ENSP00000314067.3
PAK2	ENST00000426668.1	c.62A>C	p.Gln21Pro	missense_variant	2/6	3		ENSP00000402927.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 20

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

clinical testing

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Oct 15, 2024

This variant is confirmed de novo (PS2), absent from control databases (PM2) and multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3). This variant is located in the kinase domain of PAK2 in which 4 other missense variants have been linked to Knobloch syndrome 2 (PMID 33693784, 38894571, 37808560, 38712026). In summary this variant met enough ACMG criteria to be classified as likely pathogenic (ACMG Guidelines, 2015, PMID 25741868) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.91	P
Vest4		0.85
MutPred		0.63		Gain of catalytic residue at Q279 (P = 0.057);
MVP		0.86
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.95
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr3-196539623;