rs33942096

Variant names:

• chr3-49128787-G-A
• rs33942096
• NM_002292.4:c.1764C>T

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.1764C>T​(p.Pro588Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,613,746 control chromosomes in the GnomAD database, including 463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 32)
  • Exomes 𝑓: 0.023 (430 hom.)
• Consequence: LAMB2 NM_002292.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.34

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=-0.86).
• BP6: Variant 3-49128787-G-A is Benign according to our data. Variant chr3-49128787-G-A is described in ClinVar as [Benign]. Clinvar id is 258600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49128787-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2470/152274) while in subpopulation NFE AF= 0.0254 (1726/67996). AF 95% confidence interval is 0.0244. There are 33 homozygotes in gnomad4. There are 1138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB2	NM_002292.4	c.1764C>T	p.Pro588Pro	synonymous_variant	Exon 14 of 32	ENST00000305544.9	NP_002283.3
LAMB2	XM_005265127.5	c.1764C>T	p.Pro588Pro	synonymous_variant	Exon 15 of 33		XP_005265184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMB2	ENST00000305544.9	c.1764C>T	p.Pro588Pro	synonymous_variant	Exon 14 of 32	1	NM_002292.4	ENSP00000307156.4
LAMB2	ENST00000418109.5	c.1764C>T	p.Pro588Pro	synonymous_variant	Exon 15 of 33	1		ENSP00000388325.1
LAMB2	ENST00000483321.1	n.194C>T		non_coding_transcript_exon_variant	Exon 3 of 3	3
LAMB2	ENST00000488638.1	n.-47C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2470 AN: 152156 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0165 AC: 4141 AN: 251034 Hom.: 47 AF XY: 0.0163 AC XY: 2217 AN XY: 135698

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.0317

Gnomad NFE exome AF: 0.0254

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.0228 AC: 33359 AN: 1461472 Hom.: 430 Cov.: 36 AF XY: 0.0222 AC XY: 16108 AN XY: 726994

Gnomad4 AFR exome AF: 0.00308

Gnomad4 AMR exome AF: 0.00756

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.0319

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0162 AC: 2470 AN: 152274 Hom.: 33 Cov.: 32 AF XY: 0.0153 AC XY: 1138 AN XY: 74462

Gnomad4 AFR AF: 0.00358

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0340

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.0224 Hom.: 50

Bravo AF: 0.0145

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.0214

EpiControl AF: 0.0218

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20556798) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kidney disorder Benign:1

Oct 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LAMB2-related infantile-onset nephrotic syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.86
CADD	Benign	2.0
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs33942096; hg19: chr3-49166220; COSMIC: COSV59738170; COSMIC: COSV59738170;