Genetic Variant LIMK2:p.Arg381His (chr22-31267789-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000331728.9(LIMK2):c.1142G>A(p.Arg381His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000876 in 1,598,366 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000076 ( 1 hom. )

Consequence

LIMK2
ENST00000331728.9 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.60

Publications

3 publications found

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]

LIMK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000331728.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LIMK2	NM_005569.4	MANE Select	c.1142G>A	p.Arg381His	missense	Exon 10 of 16	NP_005560.1
LIMK2	NM_001031801.2		c.1079G>A	p.Arg360His	missense	Exon 9 of 15	NP_001026971.1
LIMK2	NM_016733.3		c.1079G>A	p.Arg360His	missense	Exon 9 of 15	NP_057952.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LIMK2	ENST00000331728.9	TSL:1 MANE Select	c.1142G>A	p.Arg381His	missense	Exon 10 of 16	ENSP00000332687.4
LIMK2	ENST00000340552.4	TSL:1	c.1079G>A	p.Arg360His	missense	Exon 9 of 15	ENSP00000339916.4
LIMK2	ENST00000333611.8	TSL:1	c.1079G>A	p.Arg360His	missense	Exon 9 of 15	ENSP00000330470.4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152148

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000168

AC:

AN:

237486

AF XY:

0.00

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 FIN exome

AF:

0.0000942

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000761

AC:

AN:

1446100

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

719382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32408

American (AMR)

AF:

0.0000492

AC:

AN:

40640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25006

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

83616

European-Finnish (FIN)

AF:

0.0000377

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00000542

AC:

AN:

1106496

Other (OTH)

AF:

0.00

AC:

AN:

59690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41536

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.7

PhyloP100

9.6

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.62

MutPred

0.22

Gain of catalytic residue at L383 (P = 0.1384)

MVP

0.94

MPC

1.2

ClinPred

0.90

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.73

gMVP

0.61

Mutation Taster

=9/91

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over