rs768056213

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001161403.3(LIMS2):​c.290C>T​(p.Pro97Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

LIMS2
NM_001161403.3 missense

Scores

10
6
3

Clinical Significance

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

Conservation

PhyloP100: 9.86
Variant links:
Genes affected
LIMS2 (HGNC:16084): (LIM zinc finger domain containing 2) This gene encodes a member of a small family of focal adhesion proteins which interacts with ILK (integrin-linked kinase), a protein which effects protein-protein interactions with the extraceullar matrix. The encoded protein has five LIM domains, each domain forming two zinc fingers, which permit interactions which regulate cell shape and migration. A pseudogene of this gene is located on chromosome 4. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.919
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LIMS2NM_001161403.3 linkc.290C>T p.Pro97Leu missense_variant Exon 4 of 10 ENST00000355119.9 NP_001154875.1 Q7Z4I7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LIMS2ENST00000355119.9 linkc.290C>T p.Pro97Leu missense_variant Exon 4 of 10 1 NM_001161403.3 ENSP00000347240.4 Q7Z4I7-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251406
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000999
AC:
146
AN:
1461798
Hom.:
0
Cov.:
33
AF XY:
0.0000949
AC XY:
69
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000121
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

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

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2W Uncertain:2
Aug 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 119 of the LIMS2 protein (p.Pro119Leu). This variant is present in population databases (rs768056213, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 25589244). This variant is also known as c.356C>T, p.P119L in NM_001136037.2. ClinVar contains an entry for this variant (Variation ID: 242437). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LIMS2 protein function with a negative predictive value of 80%. 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. -

Apr 12, 2022
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
.;.;D;.;.;.
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;.;D;.;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Uncertain
2.5
.;.;M;.;.;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-7.9
D;D;D;D;D;D
REVEL
Pathogenic
0.76
Sift
Benign
0.047
D;T;T;T;T;T
Sift4G
Benign
0.095
T;T;T;T;T;T
Polyphen
1.0
D;.;D;.;.;.
Vest4
0.95
MutPred
0.67
.;.;Gain of MoRF binding (P = 0.0957);.;.;.;
MVP
0.94
MPC
0.54
ClinPred
0.89
D
GERP RS
5.4
Varity_R
0.50
gMVP
0.57

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: rs768056213; hg19: chr2-128412067; COSMIC: COSV55754983; COSMIC: COSV55754983; API