19-51380525-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001161748.2(LIM2):​c.440T>C​(p.Val147Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000731 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

LIM2
NM_001161748.2 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.30
Variant links:
Genes affected
LIM2 (HGNC:6610): (lens intrinsic membrane protein 2) This gene encodes an eye lens-specific protein found at the junctions of lens fiber cells, where it may contribute to cell junctional organization. It acts as a receptor for calmodulin, and may play an important role in both lens development and cataractogenesis. Mutations in this gene have been associated with cataract formation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.35730475).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LIM2NM_001161748.2 linkc.440T>C p.Val147Ala missense_variant Exon 4 of 5 ENST00000596399.2 NP_001155220.1 P55344-1
LIM2NM_030657.4 linkc.566T>C p.Val189Ala missense_variant Exon 4 of 5 NP_085915.2 P55344-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LIM2ENST00000596399.2 linkc.440T>C p.Val147Ala missense_variant Exon 4 of 5 1 NM_001161748.2 ENSP00000472090.2 P55344-1
LIM2ENST00000221973.7 linkc.566T>C p.Val189Ala missense_variant Exon 4 of 5 1 ENSP00000221973.2 P55344-2

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152190
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251404
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
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:
0.0000528
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000780
AC:
114
AN:
1461886
Hom.:
0
Cov.:
38
AF XY:
0.0000784
AC XY:
57
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
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:
0.0000989
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152190
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000772
Hom.:
0
Bravo
AF:
0.0000416
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
May 23, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.566T>C (p.V189A) alteration is located in exon 4 (coding exon 3) of the LIM2 gene. This alteration results from a T to C substitution at nucleotide position 566, causing the valine (V) at amino acid position 189 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cataract 19 multiple types Uncertain:1
May 17, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 189 of the LIM2 protein (p.Val189Ala). This variant is present in population databases (rs143515134, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with LIM2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
.;D
Eigen
Benign
-0.027
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.86
D;D
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.7
.;L
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.7
N;.
REVEL
Uncertain
0.34
Sift
Uncertain
0.016
D;.
Sift4G
Uncertain
0.026
D;T
Polyphen
0.072
B;B
Vest4
0.35
MVP
0.88
MPC
0.15
ClinPred
0.11
T
GERP RS
4.7
Varity_R
0.096
gMVP
0.67

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: rs143515134; hg19: chr19-51883779; API