rs201527546

Variant names:

• chr2-127657501-C-T
• rs201527546
• NM_001161403.3:c.73G>A
• LIMS2 p.Ala25Thr

Your query was ambiguous. Multiple possible variants found:

• chr2-127657501-C-T
• chr2-127657501-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001161403.3(LIMS2):​c.73G>A​(p.Ala25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,613,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A25A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: LIMS2 NM_001161403.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0110
• Publications: 2 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02268827).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161403.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIMS2	NM_001161403.3	MANE Select	c.73G>A	p.Ala25Thr	missense	Exon 2 of 10	NP_001154875.1	Q7Z4I7-1
	LIMS2	NM_017980.5		c.145G>A	p.Ala49Thr	missense	Exon 2 of 10	NP_060450.2
	LIMS2	NM_001136037.4		c.139G>A	p.Ala47Thr	missense	Exon 3 of 11	NP_001129509.2	Q7Z4I7-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIMS2	ENST00000355119.9	TSL:1 MANE Select	c.73G>A	p.Ala25Thr	missense	Exon 2 of 10	ENSP00000347240.4	Q7Z4I7-1
	LIMS2	ENST00000324938.9	TSL:1	c.145G>A	p.Ala49Thr	missense	Exon 2 of 10	ENSP00000326888.5	Q7Z4I7-2
	LIMS2	ENST00000409455.5	TSL:1	c.58G>A	p.Ala20Thr	missense	Exon 2 of 10	ENSP00000386383.1	Q7Z4I7-3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.000478

GnomAD2 exomes AF: 0.0000640 AC: 16 AN: 250006 AF XY: 0.0000813

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1460750 Hom.: 0 Cov.: 31 AF XY: 0.0000606 AC XY: 44 AN XY: 726648

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.000269 AC: 12 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1111708

Other (OTH) AF: 0.000182 AC: 11 AN: 60354

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74490

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.00118 AC: 18 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000112 Hom.: 1

Bravo AF: 0.000397

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2W (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.6
DANN	Benign	0.75
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.051	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.88	L
PhyloP100		-0.011
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.11
Sift	Benign	0.64	T
Sift4G	Benign	0.68	T
Varity_R		0.044
gMVP		0.13
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201527546;

hg19: chr2-128415075;