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GeneBe

22-31262216-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005569.4(LIMK2):​c.634G>A​(p.Val212Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000106 in 1,613,836 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

LIMK2
NM_005569.4 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.88
Variant links:
Genes affected
LIMK2 (HGNC:6614): (LIM domain kinase 2) There are approximately 40 known eukaryotic LIM proteins, so named for the LIM domains they contain. LIM domains are highly conserved cysteine-rich structures containing 2 zinc fingers. Although zinc fingers usually function by binding to DNA or RNA, the LIM motif probably mediates protein-protein interactions. LIM kinase-1 and LIM kinase-2 belong to a small subfamily with a unique combination of 2 N-terminal LIM motifs and a C-terminal protein kinase domain. The protein encoded by this gene is phosphorylated and activated by ROCK, a downstream effector of Rho, and the encoded protein, in turn, phosphorylates cofilin, inhibiting its actin-depolymerizing activity. It is thought that this pathway contributes to Rho-induced reorganization of the actin cytoskeleton. At least three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.040894568).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LIMK2NM_005569.4 linkuse as main transcriptc.634G>A p.Val212Ile missense_variant 6/16 ENST00000331728.9
LIMK2NM_001031801.2 linkuse as main transcriptc.571G>A p.Val191Ile missense_variant 5/15
LIMK2NM_016733.3 linkuse as main transcriptc.571G>A p.Val191Ile missense_variant 5/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LIMK2ENST00000331728.9 linkuse as main transcriptc.634G>A p.Val212Ile missense_variant 6/161 NM_005569.4 A1P53671-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00115
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000954
AC:
24
AN:
251470
Hom.:
0
AF XY:
0.0000956
AC XY:
13
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000105
AC:
154
AN:
1461510
Hom.:
1
Cov.:
30
AF XY:
0.0000963
AC XY:
70
AN XY:
727080
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000202
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000121
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152326
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000114
Hom.:
0
Bravo
AF:
0.0000945
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

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 GeneticsSep 07, 2022The c.571G>A (p.V191I) alteration is located in exon 5 (coding exon 5) of the LIMK2 gene. This alteration results from a G to A substitution at nucleotide position 571, causing the valine (V) at amino acid position 191 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
Benign
0.079
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
22
DANN
Benign
0.88
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.090
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.80
T;T;T;T
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.041
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.38
N;N;N;N
REVEL
Benign
0.028
Sift
Benign
0.27
T;T;T;T
Sift4G
Benign
0.28
T;T;T;T
Polyphen
0.025
B;B;.;.
Vest4
0.20
MVP
0.30
MPC
0.35
ClinPred
0.059
T
GERP RS
4.5
Varity_R
0.026
gMVP
0.26

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs369493707; hg19: chr22-31658202; API