NM_001161403.3:c.998C>T

Variant names:

• chr2-127639309-G-A
• NM_001161403.3:c.998C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001161403.3(LIMS2):​c.998C>T​(p.Pro333Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LIMS2 NM_001161403.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2W

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21464181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIMS2	NM_001161403.3	c.998C>T	p.Pro333Leu	missense_variant	Exon 10 of 10	ENST00000355119.9	NP_001154875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIMS2	ENST00000355119.9	c.998C>T	p.Pro333Leu	missense_variant	Exon 10 of 10	1	NM_001161403.3	ENSP00000347240.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1070C>T (p.P357L) alteration is located in exon 10 (coding exon 10) of the LIMS2 gene. This alteration results from a C to T substitution at nucleotide position 1070, causing the proline (P) at amino acid position 357 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	.;.;.;.;T;.;.;.;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.93	.;.;D;.;D;.;D;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.
PhyloP100		5.0
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.067
Sift	Uncertain	0.026	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.046	D;D;T;D;D;D;D;D;T;D
Polyphen		0.0010, 0.0	.;.;B;.;B;.;.;.;.;.
Vest4		0.38
MutPred		0.28		.;.;.;.;Loss of glycosylation at P333 (P = 0.0375);.;.;.;.;.;
MVP		0.66
MPC		0.42
ClinPred		0.86	D
GERP RS		3.1
Varity_R		0.066
gMVP		0.53
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

hg19: chr2-128396884;