19-51380221-G-A

Position:

chr19-51380221-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001161748.2(LIM2):c.502C>T(p.Arg168Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000121 in 1,613,762 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000076 ( 1 hom. )

Consequence

LIM2
NM_001161748.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.19

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]

LIM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015348256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIM2	NM_001161748.2 link	c.502C>T	p.Arg168Cys	missense_variant	5/5	ENST00000596399.2	NP_001155220.1	P55344-1
LIM2	NM_030657.4 link	c.628C>T	p.Arg210Cys	missense_variant	5/5		NP_085915.2	P55344-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIM2	ENST00000596399.2 link	c.502C>T	p.Arg168Cys	missense_variant	5/5	1	NM_001161748.2	ENSP00000472090.2		P55344-1
LIM2	ENST00000221973.7 link	c.628C>T	p.Arg210Cys	missense_variant	5/5	1		ENSP00000221973.2		P55344-2

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000206

AC:

AN:

248072

Hom.:

AF XY:

0.000208

AC XY:

AN XY:

134320

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000979

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000720

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.0000759

AC:

111

AN:

1461610

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000806

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000559

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.000434

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.0000724

Hom.:

Bravo

AF:

0.00105

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000109

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.628C>T (p.R210C) alteration is located in exon 5 (coding exon 4) of the LIM2 gene. This alteration results from a C to T substitution at nucleotide position 628, causing the arginine (R) at amino acid position 210 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cataract 19 multiple types

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

ClinVar contains an entry for this variant (Variation ID: 1430326). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 210 of the LIM2 protein (p.Arg210Cys). This variant is present in population databases (rs150085001, gnomAD 0.1%). 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 disruptive. 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

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

.;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.0

.;M

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.54

P;D

Vest4

0.27

MVP

0.68

MPC

0.57

ClinPred

0.11

GERP RS

4.1

Varity_R

0.093

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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