rs34290943

Variant names:

• chr3-49124227-T-C
• rs34290943
• NM_002292.4:c.3387A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002292.4(LAMB2):​c.3387A>G​(p.Gln1129Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,614,016 control chromosomes in the GnomAD database, including 12,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (931 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11562 hom.)
• Consequence: LAMB2 NM_002292.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.789
• Publications: 21 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, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet
• LAMB2-related infantile-onset nephrotic syndrome

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 3-49124227-T-C is Benign according to our data. Variant chr3-49124227-T-C is described in ClinVar as Benign. ClinVar VariationId is 258608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.789 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

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.3387A>G	p.Gln1129Gln	synonymous	Exon 23 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.3387A>G	p.Gln1129Gln	synonymous	Exon 23 of 32	ENSP00000307156.4
	LAMB2	ENST00000418109.5	TSL:1	c.3387A>G	p.Gln1129Gln	synonymous	Exon 24 of 33	ENSP00000388325.1
	LAMB2	ENST00000960189.1		c.3429A>G	p.Gln1143Gln	synonymous	Exon 23 of 32	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.0920 AC: 13994 AN: 152154 Hom.: 930 Cov.: 33

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0670

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0788

GnomAD2 exomes AF: 0.109 AC: 27299 AN: 251184 AF XY: 0.115

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.0512

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.118 AC: 172833 AN: 1461744 Hom.: 11562 Cov.: 36 AF XY: 0.120 AC XY: 87401 AN XY: 727178

African (AFR) AF: 0.0162 AC: 543 AN: 33480

American (AMR) AF: 0.0518 AC: 2318 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6103 AN: 26136

East Asian (EAS) AF: 0.00118 AC: 47 AN: 39700

South Asian (SAS) AF: 0.158 AC: 13619 AN: 86254

European-Finnish (FIN) AF: 0.170 AC: 9048 AN: 53316

Middle Eastern (MID) AF: 0.160 AC: 920 AN: 5768

European-Non Finnish (NFE) AF: 0.120 AC: 132927 AN: 1111978

Other (OTH) AF: 0.121 AC: 7308 AN: 60392

GnomAD4 genome AF: 0.0919 AC: 13992 AN: 152272 Hom.: 931 Cov.: 33 AF XY: 0.0953 AC XY: 7092 AN XY: 74446

African (AFR) AF: 0.0190 AC: 791 AN: 41584

American (AMR) AF: 0.0669 AC: 1024 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3470

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5170

South Asian (SAS) AF: 0.145 AC: 703 AN: 4832

European-Finnish (FIN) AF: 0.188 AC: 1995 AN: 10602

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8393 AN: 67988

Other (OTH) AF: 0.0784 AC: 166 AN: 2116

Alfa AF: 0.118 Hom.: 687

Bravo AF: 0.0760

Asia WGS AF: 0.0610 AC: 217 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.116

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.60
CADD	Benign	3.0
DANN	Benign	0.56
PhyloP100		0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34290943; hg19: chr3-49161660;