19-51380504-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_001161748.2(LIM2):​c.460+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LIM2
NM_001161748.2 splice_donor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.09
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_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.25862068 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.7, offset of 24, new splice context is: aagGTcagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LIM2NM_001161748.2 linkc.460+1G>A splice_donor_variant, intron_variant Intron 4 of 4 ENST00000596399.2 NP_001155220.1 P55344-1
LIM2NM_030657.4 linkc.586+1G>A splice_donor_variant, intron_variant Intron 4 of 4 NP_085915.2 P55344-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LIM2ENST00000596399.2 linkc.460+1G>A splice_donor_variant, intron_variant Intron 4 of 4 1 NM_001161748.2 ENSP00000472090.2 P55344-1
LIM2ENST00000221973.7 linkc.586+1G>A splice_donor_variant, intron_variant Intron 4 of 4 1 ENSP00000221973.2 P55344-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251350
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461886
Hom.:
0
Cov.:
38
AF XY:
0.00000138
AC XY:
1
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cataract 19 multiple types Uncertain:1
Sep 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 4 of the LIM2 gene. It does not directly change the encoded amino acid sequence of the LIM2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with LIM2-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.87
D
GERP RS
4.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.67
Position offset: -23
DS_DL_spliceai
0.99
Position offset: 1

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: rs1252487147; hg19: chr19-51883758; API