2-127639425-G-T

Position:

chr2-127639425-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001161403.3(LIMS2):c.882C>A(p.Asn294Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000457 in 1,613,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

LIMS2
NM_001161403.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.78

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]

LIMS2 links:

LIMS2 (HGNC:):

LIMS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.066885024).

BP6

Variant 2-127639425-G-T is Benign according to our data. Variant chr2-127639425-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542250.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIMS2	NM_001161403.3 linkuse as main transcript	c.882C>A	p.Asn294Lys	missense_variant	10/10	ENST00000355119.9	NP_001154875.1	Q7Z4I7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIMS2	ENST00000355119.9 linkuse as main transcript	c.882C>A	p.Asn294Lys	missense_variant	10/10	1	NM_001161403.3	ENSP00000347240.4		Q7Z4I7-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000454

AC:

113

AN:

249016

Hom.:

AF XY:

0.000438

AC XY:

AN XY:

134678

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000475

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000465

AC:

679

AN:

1461354

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

340

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.000504

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000388

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000632

Hom.:

Bravo

AF:

0.000450

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.000535

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2W

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 316 of the LIMS2 protein (p.Asn316Lys). This variant is present in population databases (rs149101001, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LIMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 542250). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;.;.;.;T;.;.;.;.;.

Eigen

Benign

0.067

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

.;.;D;.;D;.;D;.;D;D

M_CAP

Benign

0.060

MetaRNN

Benign

0.067

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;.;.;.;L;.;.;.;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.8

N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.51

Sift

Benign

0.047

D;D;T;D;D;D;D;D;T;D

Sift4G

Benign

0.22

T;T;T;T;T;T;T;T;T;T

Polyphen

1.0, 1.0

.;.;D;.;D;.;.;.;.;.

Vest4

0.54

MutPred

0.60

.;.;.;.;Gain of methylation at N294 (P = 0.0247);.;.;.;.;.;

MVP

0.87

MPC

0.57

ClinPred

0.060

GERP RS

4.0

Varity_R

0.23

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over