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GeneBe

3-196812239-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002577.4(PAK2):c.794C>T(p.Thr265Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,593,270 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 1 hom. )

Consequence

PAK2
NM_002577.4 missense

Scores

3
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.63
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAK2NM_002577.4 linkuse as main transcriptc.794C>T p.Thr265Ile missense_variant 9/15 ENST00000327134.7
PAK2XM_011512870.3 linkuse as main transcriptc.794C>T p.Thr265Ile missense_variant 9/15
PAK2XM_047448218.1 linkuse as main transcriptc.794C>T p.Thr265Ile missense_variant 9/15
PAK2XM_047448219.1 linkuse as main transcriptc.794C>T p.Thr265Ile missense_variant 9/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAK2ENST00000327134.7 linkuse as main transcriptc.794C>T p.Thr265Ile missense_variant 9/152 NM_002577.4 P1
PAK2ENST00000426668.1 linkuse as main transcriptc.23C>T p.Thr8Ile missense_variant 1/63

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152096
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000459
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250550
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135724
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000139
AC:
20
AN:
1441056
Hom.:
1
Cov.:
25
AF XY:
0.0000167
AC XY:
12
AN XY:
718318
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000183
Gnomad4 OTH exome
AF:
0.000302
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000459
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 12, 2021The c.794C>T (p.T265I) alteration is located in exon 9 (coding exon 8) of the PAK2 gene. This alteration results from a C to T substitution at nucleotide position 794, causing the threonine (T) at amino acid position 265 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Benign
-0.030
T
BayesDel_noAF
Benign
-0.28
Cadd
Uncertain
25
Dann
Uncertain
0.98
DEOGEN2
Benign
0.29
T
Eigen
Benign
-0.052
Eigen_PC
Benign
0.14
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.036
D
MetaRNN
Uncertain
0.51
D
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
0.40
N
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-4.7
D
REVEL
Benign
0.24
Sift
Benign
0.096
T
Sift4G
Benign
0.24
T
Polyphen
0.039
B
Vest4
0.63
MutPred
0.46
Loss of glycosylation at S260 (P = 0.1337);
MVP
0.50
MPC
1.2
ClinPred
0.57
D
GERP RS
5.0
Varity_R
0.41
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767122683; hg19: chr3-196539110; API