2-127639336-G-A

Position:

• chr2-127639336-G-A

Variant summary

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

The NM_001161403.3(LIMS2):​c.971C>T​(p.Ser324Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000595 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: LIMS2 NM_001161403.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.89

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=0.03428644).
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIMS2	NM_001161403.3	c.971C>T	p.Ser324Leu	missense_variant	10/10	ENST00000355119.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIMS2	ENST00000355119.9	c.971C>T	p.Ser324Leu	missense_variant	10/10	1	NM_001161403.3	P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251258 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135804

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461652 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727148

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74436

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000161 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 346 of the LIMS2 protein (p.Ser346Leu). This variant is present in population databases (rs377574169, gnomAD 0.09%), 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: 1354331). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Pathogenic	1.0
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.034	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.24	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T;T;T
Polyphen		0.23, 0.52	.;.;B;.;P;.;.;.;.;.
Vest4		0.36
MVP		0.57
MPC		0.14
ClinPred		0.030	T
GERP RS		5.1
Varity_R		0.18
gMVP		0.38

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: rs377574169; hg19: chr2-128396911; COSMIC: COSV61441228; COSMIC: COSV61441228;