rs34290943

Positions:

• chr3-49124227-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002292.4(LAMB2):​c.3387A>G​(p.Gln1129=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 258608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49124227-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB2	NM_002292.4	c.3387A>G	p.Gln1129=	synonymous_variant	23/32	ENST00000305544.9	NP_002283.3
LAMB2	XM_005265127.5	c.3387A>G	p.Gln1129=	synonymous_variant	24/33		XP_005265184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB2	ENST00000305544.9	c.3387A>G	p.Gln1129=	synonymous_variant	23/32	1	NM_002292.4	ENSP00000307156	P1
LAMB2	ENST00000418109.5	c.3387A>G	p.Gln1129=	synonymous_variant	24/33	1		ENSP00000388325	P1
LAMB2	ENST00000480640.1	n.145A>G		non_coding_transcript_exon_variant	2/3	3
LAMB2	ENST00000538659.1	n.397A>G		non_coding_transcript_exon_variant	1/2	2

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

GnomAD3 exomes AF: 0.109 AC: 27299 AN: 251184 Hom.: 1963 AF XY: 0.115 AC XY: 15663 AN XY: 135826

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 SAS exome AF: 0.154

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

Gnomad4 AFR exome AF: 0.0162

Gnomad4 AMR exome AF: 0.0518

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.00118

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.121

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

Gnomad4 AFR AF: 0.0190

Gnomad4 AMR AF: 0.0669

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.0784

Alfa AF: 0.119 Hom.: 557

Bravo AF: 0.0760

Asia WGS AF: 0.0610 AC: 217 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.116

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Pierson syndrome;C3280113:LAMB2-related infantile-onset nephrotic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

LAMB2-related infantile-onset nephrotic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pierson syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.0
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs34290943; hg19: chr3-49161660;