chr2-127643047-G-A

Variant names:

• chr2-127643047-G-A
• rs145123078
• ENST00000409754.5:c.-72C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001256542.2(LIMS2):​c.-72C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00515 in 1,585,184 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0051 (27 hom.)
• Consequence: LIMS2 NM_001256542.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009791315).
• BP6: Variant 2-127643047-G-A is Benign according to our data. Variant chr2-127643047-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256542.2. 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>T	p.Arg129Cys	missense	Exon 5 of 10	NP_001154875.1	Q7Z4I7-1
	LIMS2	NM_001256542.2		c.-72C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001243471.1	Q7Z4I7-4
	LIMS2	NM_017980.5		c.457C>T	p.Arg153Cys	missense	Exon 5 of 10	NP_060450.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIMS2	ENST00000409754.5	TSL:1	c.-72C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	ENSP00000386345.1	Q7Z4I7-4
	LIMS2	ENST00000355119.9	TSL:1 MANE Select	c.385C>T	p.Arg129Cys	missense	Exon 5 of 10	ENSP00000347240.4	Q7Z4I7-1
	LIMS2	ENST00000324938.9	TSL:1	c.457C>T	p.Arg153Cys	missense	Exon 5 of 10	ENSP00000326888.5	Q7Z4I7-2

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 847 AN: 152258 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00504 AC: 1017 AN: 201794 AF XY: 0.00513

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.000220

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00367

GnomAD4 exome AF: 0.00510 AC: 7307 AN: 1432808 Hom.: 27 Cov.: 34 AF XY: 0.00521 AC XY: 3696 AN XY: 710014

African (AFR) AF: 0.00682 AC: 225 AN: 32998

American (AMR) AF: 0.00151 AC: 61 AN: 40380

Ashkenazi Jewish (ASJ) AF: 0.0000783 AC: 2 AN: 25552

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38266

South Asian (SAS) AF: 0.00647 AC: 530 AN: 81902

European-Finnish (FIN) AF: 0.0129 AC: 650 AN: 50414

Middle Eastern (MID) AF: 0.00301 AC: 17 AN: 5640

European-Non Finnish (NFE) AF: 0.00509 AC: 5593 AN: 1098360

Other (OTH) AF: 0.00385 AC: 228 AN: 59296

GnomAD4 genome AF: 0.00557 AC: 849 AN: 152376 Hom.: 2 Cov.: 34 AF XY: 0.00553 AC XY: 412 AN XY: 74508

African (AFR) AF: 0.00639 AC: 266 AN: 41596

American (AMR) AF: 0.00235 AC: 36 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4828

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00572 AC: 389 AN: 68040

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00532 Hom.: 5

Bravo AF: 0.00478

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00843 AC: 37

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00483 AC: 579

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2W (1)
-	-	1	LIMS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	0.085
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.046	D
Polyphen		0.010	B
Vest4		0.63
MVP		0.90
MPC		0.50
ClinPred		0.031	T
GERP RS		4.4
PromoterAI		-0.029	Neutral
Varity_R		0.50
gMVP		0.62
Mutation Taster		=291/9	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; COSMIC: COSV106084532; COSMIC: COSV106084532;