22-31225809-T-C

Position:

• chr22-31225809-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005569.4(LIMK2):​c.106T>C​(p.Ser36Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIMK2 NM_005569.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIMK2	NM_005569.4	c.106T>C	p.Ser36Pro	missense_variant	2/16	ENST00000331728.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIMK2	ENST00000331728.9	c.106T>C	p.Ser36Pro	missense_variant	2/16	1	NM_005569.4	A1
LIMK2	ENST00000406516.5	c.-119+13385T>C		intron_variant		5
LIMK2	ENST00000462625.1	n.276T>C		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.106T>C (p.S36P) alteration is located in exon 2 (coding exon 2) of the LIMK2 gene. This alteration results from a T to C substitution at nucleotide position 106, causing the serine (S) at amino acid position 36 to be replaced by a proline (P). 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	0.086
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.050
Eigen_PC	Benign	0.051
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.94	D;D;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.014	D
Sift4G	Benign	0.065	T
Polyphen		0.77	P
Vest4		0.65
MutPred		0.63		Gain of catalytic residue at S36 (P = 0.009);
MVP		0.92
ClinPred		0.44	T
GERP RS		4.6
Varity_R		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr22-31621795;