rs34967349

chr3-49123571-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002292.4(LAMB2):c.3858G>T(p.Val1286=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,614,190 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (20 hom.)
• Consequence: LAMB2 NM_002292.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.00

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=-0.48).
• BP6: Variant 3-49123571-C-A is Benign according to our data. Variant chr3-49123571-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 472482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49123571-C-A is described in Lovd as [Benign]. Variant chr3-49123571-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00309 (470/152338) while in subpopulation NFE AF= 0.00454 (309/68024). AF 95% confidence interval is 0.00413. There are 2 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB2	NM_002292.4	c.3858G>T	p.Val1286=	synonymous_variant	25/32	ENST00000305544.9
LAMB2	XM_005265127.5	c.3858G>T	p.Val1286=	synonymous_variant	26/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB2	ENST00000305544.9	c.3858G>T	p.Val1286=	synonymous_variant	25/32	1	NM_002292.4	P1
LAMB2	ENST00000418109.5	c.3858G>T	p.Val1286=	synonymous_variant	26/33	1		P1
LAMB2	ENST00000469665.1	n.88G>T		non_coding_transcript_exon_variant	2/3	2
LAMB2	ENST00000477225.1	n.289G>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 470 AN: 152220 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00392

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00306 AC: 769 AN: 251472 Hom.: 1 AF XY: 0.00308 AC XY: 418 AN XY: 135910

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00487 AC: 7118 AN: 1461852 Hom.: 20 Cov.: 34 AF XY: 0.00473 AC XY: 3443 AN XY: 727230

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000450

Gnomad4 NFE exome AF: 0.00585

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.00309 AC: 470 AN: 152338 Hom.: 2 Cov.: 33 AF XY: 0.00283 AC XY: 211 AN XY: 74502

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00454

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00451 Hom.: 2

Bravo AF: 0.00353

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00498

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LAMB2: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 19, 2019	- -

Pierson syndrome;C3280113:LAMB2-related infantile-onset nephrotic syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 03, 2017

- -

LAMB2-related infantile-onset nephrotic syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pierson syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	1.3
Dann	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs34967349; hg19: chr3-49161004;