2-127640153-G-C

Variant names:

• chr2-127640153-G-C
• rs115961120
• NM_001161403.3:c.803-8C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001161403.3(LIMS2):​c.803-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,613,234 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 33)
  • Exomes 𝑓: 0.018 (279 hom.)
• Consequence: LIMS2 NM_001161403.3 splice_region, intron
• Scores: Splicing: ADA: 0.02291
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.59
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-127640153-G-C is Benign according to our data. Variant chr2-127640153-G-C is described in ClinVar as Benign. ClinVar VariationId is 260989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.014 (2133/152348) while in subpopulation NFE AF = 0.02 (1358/68026). AF 95% confidence interval is 0.0191. There are 23 homozygotes in GnomAd4. There are 989 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR,Unknown gene

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.803-8C>G		splice_region intron	N/A	NP_001154875.1
	LIMS2	NM_017980.5		c.875-8C>G		splice_region intron	N/A	NP_060450.2
	LIMS2	NM_001136037.4		c.869-8C>G		splice_region intron	N/A	NP_001129509.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIMS2	ENST00000355119.9	TSL:1 MANE Select	c.803-8C>G		splice_region intron	N/A	ENSP00000347240.4
	LIMS2	ENST00000324938.9	TSL:1	c.875-8C>G		splice_region intron	N/A	ENSP00000326888.5
	LIMS2	ENST00000409455.5	TSL:1	c.788-8C>G		splice_region intron	N/A	ENSP00000386383.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2132 AN: 152230 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0141 AC: 3535 AN: 250628 AF XY: 0.0138

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0349

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00786

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0244

GnomAD4 exome AF: 0.0177 AC: 25925 AN: 1460886 Hom.: 279 Cov.: 32 AF XY: 0.0177 AC XY: 12849 AN XY: 726748

African (AFR) AF: 0.00287 AC: 96 AN: 33478

American (AMR) AF: 0.0171 AC: 766 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 973 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00477 AC: 411 AN: 86250

European-Finnish (FIN) AF: 0.00806 AC: 424 AN: 52618

Middle Eastern (MID) AF: 0.0100 AC: 57 AN: 5680

European-Non Finnish (NFE) AF: 0.0199 AC: 22102 AN: 1111940

Other (OTH) AF: 0.0181 AC: 1095 AN: 60370

GnomAD4 genome AF: 0.0140 AC: 2133 AN: 152348 Hom.: 23 Cov.: 33 AF XY: 0.0133 AC XY: 989 AN XY: 74494

African (AFR) AF: 0.00435 AC: 181 AN: 41576

American (AMR) AF: 0.0180 AC: 275 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4830

European-Finnish (FIN) AF: 0.00734 AC: 78 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0200 AC: 1358 AN: 68026

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0156 Hom.: 14

Bravo AF: 0.0150

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.7
DANN	Benign	0.53
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.023
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.060		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: rs115961120; hg19: chr2-128397728;