2-127643033-C-T

Variant names:

• chr2-127643033-C-T
• rs4662751
• NM_001161403.3:c.399G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001161403.3(LIMS2):​c.399G>A​(p.Lys133Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 1,585,692 control chromosomes in the GnomAD database, including 229,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21321 hom., cov: 35)
  • Exomes 𝑓: 0.54 (208238 hom.)
• Consequence: LIMS2 NM_001161403.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.633
• Publications: 13 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-127643033-C-T is Benign according to our data. Variant chr2-127643033-C-T is described in ClinVar as Benign. ClinVar VariationId is 260987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.633 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

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.399G>A	p.Lys133Lys	synonymous	Exon 5 of 10	NP_001154875.1	Q7Z4I7-1
	LIMS2	NM_017980.5		c.471G>A	p.Lys157Lys	synonymous	Exon 5 of 10	NP_060450.2
	LIMS2	NM_001136037.4		c.465G>A	p.Lys155Lys	synonymous	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.399G>A	p.Lys133Lys	synonymous	Exon 5 of 10	ENSP00000347240.4	Q7Z4I7-1
	LIMS2	ENST00000324938.9	TSL:1	c.471G>A	p.Lys157Lys	synonymous	Exon 5 of 10	ENSP00000326888.5	Q7Z4I7-2
	LIMS2	ENST00000409455.5	TSL:1	c.384G>A	p.Lys128Lys	synonymous	Exon 5 of 10	ENSP00000386383.1	Q7Z4I7-3

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79872 AN: 152026 Hom.: 21306 Cov.: 35

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.535

GnomAD2 exomes AF: 0.557 AC: 114041 AN: 204722 AF XY: 0.544

Gnomad AFR exome AF: 0.468

Gnomad AMR exome AF: 0.726

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.545

GnomAD4 exome AF: 0.535 AC: 767440 AN: 1433546 Hom.: 208238 Cov.: 54 AF XY: 0.532 AC XY: 377990 AN XY: 710416

African (AFR) AF: 0.469 AC: 15477 AN: 32988

American (AMR) AF: 0.715 AC: 29049 AN: 40616

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 15533 AN: 25576

East Asian (EAS) AF: 0.755 AC: 28986 AN: 38370

South Asian (SAS) AF: 0.451 AC: 36977 AN: 82026

European-Finnish (FIN) AF: 0.531 AC: 26911 AN: 50720

Middle Eastern (MID) AF: 0.551 AC: 3127 AN: 5678

European-Non Finnish (NFE) AF: 0.527 AC: 579338 AN: 1098284

Other (OTH) AF: 0.540 AC: 32042 AN: 59288

GnomAD4 genome AF: 0.525 AC: 79908 AN: 152146 Hom.: 21321 Cov.: 35 AF XY: 0.526 AC XY: 39135 AN XY: 74374

African (AFR) AF: 0.468 AC: 19425 AN: 41512

American (AMR) AF: 0.615 AC: 9397 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2143 AN: 3470

East Asian (EAS) AF: 0.707 AC: 3656 AN: 5174

South Asian (SAS) AF: 0.453 AC: 2186 AN: 4822

European-Finnish (FIN) AF: 0.534 AC: 5654 AN: 10590

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.524 AC: 35617 AN: 67970

Other (OTH) AF: 0.529 AC: 1118 AN: 2112

Alfa AF: 0.530 Hom.: 10067

Bravo AF: 0.534

Asia WGS AF: 0.553 AC: 1929 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		0.63
PromoterAI		0.013	Neutral
Mutation Taster		=93/7	polymorphism (auto)

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: rs4662751; hg19: chr2-128400608; COSMIC: COSV55754354; COSMIC: COSV55754354;