rs145123078

chr2-127643047-G-Achr2-127643047-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001161403.3(LIMS2):c.385C>T(p.Arg129Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00515 in 1,585,184 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R129G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0051 (27 hom.)
• Consequence: LIMS2 NM_001161403.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.49

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009791315).
• BP6: Variant 2-127643047-G-A is Benign according to our data. Variant chr2-127643047-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127643047-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 847 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIMS2	NM_001161403.3	c.385C>T	p.Arg129Cys	missense_variant	5/10	ENST00000355119.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIMS2	ENST00000355119.9	c.385C>T	p.Arg129Cys	missense_variant	5/10	1	NM_001161403.3	P1

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 847 AN: 152258 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00504 AC: 1017 AN: 201794 Hom.: 3 AF XY: 0.00513 AC XY: 557 AN XY: 108576

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.000220

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00686

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00367

GnomAD4 exome AF: 0.00510 AC: 7307 AN: 1432808 Hom.: 27 Cov.: 34 AF XY: 0.00521 AC XY: 3696 AN XY: 710014

Gnomad4 AFR exome AF: 0.00682

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.0000783

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.00647

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.00509

Gnomad4 OTH exome AF: 0.00385

GnomAD4 genome AF: 0.00557 AC: 849 AN: 152376 Hom.: 2 Cov.: 34 AF XY: 0.00553 AC XY: 412 AN XY: 74508

Gnomad4 AFR AF: 0.00639

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00572

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00473 Hom.: 2

Bravo AF: 0.00478

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00843 AC: 37

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00483 AC: 579

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LIMS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

LIMS2: BS2 -

Autosomal recessive limb-girdle muscular dystrophy type 2W Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Benign	0.085
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;.;D;.;D;D
MetaRNN	Benign	0.0098	T;T;T;T;T;T
MetaSVM	Uncertain	0.65	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D;D;D;D;D;D
Sift4G	Uncertain	0.046	D;D;D;D;D;D
Polyphen		0.010	B;.;B;.;.;.
Vest4		0.63
MVP		0.90
MPC		0.50
ClinPred		0.031	T
GERP RS		4.4
Varity_R		0.50
gMVP		0.62

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

Other links and lift over

dbSNP: rs145123078; hg19: chr2-128400622;