rs144092322

Variant names:

• chr3-49125300-G-A
• rs144092322
• NM_002292.4:c.2673C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-49125300-G-A
• chr3-49125300-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002292.4(LAMB2):​c.2673C>T​(p.Gly891Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,910 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (6 hom., cov: 33)
  • Exomes 𝑓: 0.011 (123 hom.)
• Consequence: LAMB2 NM_002292.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0150
• Publications: 6 publications found

Genes affected

LAMB2 (HGNC:6487): (laminin subunit beta 2) Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins, composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively), form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the beta chain isoform laminin, beta 2. The beta 2 chain contains the 7 structural domains typical of beta chains of laminin, including the short alpha region. However, unlike beta 1 chain, beta 2 has a more restricted tissue distribution. It is enriched in the basement membrane of muscles at the neuromuscular junctions, kidney glomerulus and vascular smooth muscle. Transgenic mice in which the beta 2 chain gene was inactivated by homologous recombination, showed defects in the maturation of neuromuscular junctions and impairment of glomerular filtration. Alternative splicing involving a non consensus 5' splice site (gc) in the 5' UTR of this gene has been reported. It was suggested that inefficient splicing of this first intron, which does not change the protein sequence, results in a greater abundance of the unspliced form of the transcript than the spliced form. The full-length nature of the spliced transcript is not known. [provided by RefSeq, Aug 2011]

LAMB2 Gene-Disease associations (from GenCC):

• Pierson syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• LAMB2-related infantile-onset nephrotic syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-49125300-G-A is Benign according to our data. Variant chr3-49125300-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258604.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 = 0.00754 (1149/152334) while in subpopulation NFE AF = 0.0111 (758/68032). AF 95% confidence interval is 0.0105. There are 6 homozygotes in GnomAd4. There are 546 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002292.4. 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
	LAMB2	NM_002292.4	MANE Select	c.2673C>T	p.Gly891Gly	synonymous	Exon 19 of 32	NP_002283.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB2	ENST00000305544.9	TSL:1 MANE Select	c.2673C>T	p.Gly891Gly	synonymous	Exon 19 of 32	ENSP00000307156.4	P55268
	LAMB2	ENST00000418109.5	TSL:1	c.2673C>T	p.Gly891Gly	synonymous	Exon 20 of 33	ENSP00000388325.1	P55268
	LAMB2	ENST00000960189.1		c.2715C>T	p.Gly905Gly	synonymous	Exon 19 of 32	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.00756 AC: 1150 AN: 152216 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00866 AC: 2176 AN: 251252 AF XY: 0.00933

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00760

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00485

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0109 AC: 15996 AN: 1461576 Hom.: 123 Cov.: 35 AF XY: 0.0109 AC XY: 7890 AN XY: 727088

African (AFR) AF: 0.00242 AC: 81 AN: 33480

American (AMR) AF: 0.00818 AC: 366 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 505 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00645 AC: 556 AN: 86258

European-Finnish (FIN) AF: 0.00540 AC: 287 AN: 53108

Middle Eastern (MID) AF: 0.0480 AC: 277 AN: 5768

European-Non Finnish (NFE) AF: 0.0118 AC: 13154 AN: 1112010

Other (OTH) AF: 0.0127 AC: 768 AN: 60392

GnomAD4 genome AF: 0.00754 AC: 1149 AN: 152334 Hom.: 6 Cov.: 33 AF XY: 0.00733 AC XY: 546 AN XY: 74484

African (AFR) AF: 0.00240 AC: 100 AN: 41582

American (AMR) AF: 0.00810 AC: 124 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4828

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10622

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 758 AN: 68032

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.0100 Hom.: 5

Bravo AF: 0.00815

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	LAMB2-related infantile-onset nephrotic syndrome (1)
-	-	1	not specified (1)
-	-	1	Pierson syndrome (1)
-	-	1	Pierson syndrome;C3280113:LAMB2-related infantile-onset nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.77
PhyloP100		0.015
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144092322; hg19: chr3-49162733;