2-127643047-G-C

Variant names:

• chr2-127643047-G-C
• rs145123078
• NM_001161403.3:c.385C>G

Variant summary

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

The NM_001161403.3(LIMS2):​c.385C>G​(p.Arg129Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000126 in 1,585,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R129H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: LIMS2 NM_001161403.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.49
• Publications: 8 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: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.385C>G	p.Arg129Gly	missense	Exon 5 of 10	NP_001154875.1	Q7Z4I7-1
	LIMS2	NM_017980.5		c.457C>G	p.Arg153Gly	missense	Exon 5 of 10	NP_060450.2
	LIMS2	NM_001136037.4		c.451C>G	p.Arg151Gly	missense	Exon 6 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.385C>G	p.Arg129Gly	missense	Exon 5 of 10	ENSP00000347240.4	Q7Z4I7-1
	LIMS2	ENST00000324938.9	TSL:1	c.457C>G	p.Arg153Gly	missense	Exon 5 of 10	ENSP00000326888.5	Q7Z4I7-2
	LIMS2	ENST00000409455.5	TSL:1	c.370C>G	p.Arg124Gly	missense	Exon 5 of 10	ENSP00000386383.1	Q7Z4I7-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432814 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 710018

African (AFR) AF: 0.0000303 AC: 1 AN: 33000

American (AMR) AF: 0.00 AC: 0 AN: 40380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25552

East Asian (EAS) AF: 0.00 AC: 0 AN: 38266

South Asian (SAS) AF: 0.00 AC: 0 AN: 81902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098364

Other (OTH) AF: 0.00 AC: 0 AN: 59296

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74380

African (AFR) AF: 0.0000241 AC: 1 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 5

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2W (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.030
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.51
Sift	Benign	0.036	D
Sift4G	Benign	0.31	T
Polyphen		0.37	B
Vest4		0.56
MutPred		0.52		Loss of MoRF binding (P = 0.0461)
MVP		0.89
MPC		0.27
ClinPred		0.99	D
GERP RS		4.4
PromoterAI		-0.019	Neutral
Varity_R		0.73
gMVP		0.62
Mutation Taster		=82/18	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

dbSNP: rs145123078; hg19: chr2-128400622;