rs968524490

chr2-127664310-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000324938.9(LIMS2):c.79A>G(p.Thr27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,233,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: LIMS2 ENST00000324938.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.315

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03418675).
• BS2: High AC in GnomAd at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIMS2	NM_001161403.3	c.12-6748A>G		intron_variant		ENST00000355119.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIMS2	ENST00000355119.9	c.12-6748A>G		intron_variant		1	NM_001161403.3	P1

Frequencies

GnomAD3 genomes AF: 0.000402 AC: 61 AN: 151690 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000810

Gnomad OTH AF: 0.000481

GnomAD4 exome AF: 0.000500 AC: 541 AN: 1081530 Hom.: 0 Cov.: 31 AF XY: 0.000539 AC XY: 277 AN XY: 514030

Gnomad4 AFR exome AF: 0.0000894

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000450

Gnomad4 FIN exome AF: 0.0000467

Gnomad4 NFE exome AF: 0.000570

Gnomad4 OTH exome AF: 0.000279

GnomAD4 genome AF: 0.000402 AC: 61 AN: 151690 Hom.: 0 Cov.: 32 AF XY: 0.000351 AC XY: 26 AN XY: 74082

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000810

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000529 Hom.: 0

Bravo AF: 0.000351

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2018

This sequence change replaces threonine with alanine at codon 27 of the LIMS2 protein (p.Thr27Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with LIMS2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	Benign	-0.63	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.8
Dann	Benign	0.26
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.094	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.0050
Sift	Benign	0.76	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.037
MutPred		0.35		Loss of glycosylation at T27 (P = 0.008);
MVP		0.030
MPC		0.10
ClinPred		0.040	T
GERP RS		-1.7
gMVP		0.31

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: rs968524490; hg19: chr2-128421884;