22-31262216-G-A
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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
NM_005569.4 missense
Scores
1
16
Clinical Significance
Conservation
PhyloP100: 5.88
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]
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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 |
---|---|---|---|---|---|---|---|
LIMK2 | NM_005569.4 | c.634G>A | p.Val212Ile | missense_variant | 6/16 | ENST00000331728.9 | |
LIMK2 | NM_001031801.2 | c.571G>A | p.Val191Ile | missense_variant | 5/15 | ||
LIMK2 | NM_016733.3 | c.571G>A | p.Val191Ile | missense_variant | 5/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIMK2 | ENST00000331728.9 | c.634G>A | p.Val212Ile | missense_variant | 6/16 | 1 | NM_005569.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000954 AC: 24AN: 251470Hom.: 0 AF XY: 0.0000956 AC XY: 13AN XY: 135916
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GnomAD4 exome AF: 0.000105 AC: 154AN: 1461510Hom.: 1 Cov.: 30 AF XY: 0.0000963 AC XY: 70AN XY: 727080
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74492
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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 submitter | clinical testing | Ambry Genetics | Sep 07, 2022 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;B;.;.
Vest4
MVP
MPC
0.35
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at