3-49128787-G-A

Position:

chr3-49128787-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002292.4(LAMB2):c.1764C>T(p.Pro588=) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.34

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
LAMB2	NM_002292.4 linkuse as main transcript	c.1764C>T	p.Pro588=	synonymous_variant	14/32	ENST00000305544.9
LAMB2	XM_005265127.5 linkuse as main transcript	c.1764C>T	p.Pro588=	synonymous_variant	15/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LAMB2	ENST00000305544.9 linkuse as main transcript	c.1764C>T	p.Pro588=	synonymous_variant	14/32	1	NM_002292.4	P1
LAMB2	ENST00000418109.5 linkuse as main transcript	c.1764C>T	p.Pro588=	synonymous_variant	15/33	1		P1
LAMB2	ENST00000483321.1 linkuse as main transcript	n.194C>T		non_coding_transcript_exon_variant	3/3	3
LAMB2	ENST00000488638.1 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2470

AN:

152156

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0163

AC XY:

2217

AN XY:

135698

show subpopulations

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.:

AF XY:

0.0222

AC XY:

16108

AN XY:

726994

show subpopulations

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.:

Cov.:

AF XY:

0.0153

AC XY:

1138

AN XY:

74462

show subpopulations

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.:

Bravo

AF:

0.0145

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0214

EpiControl

AF:

0.0218

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 25, 2022	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2021	This variant is associated with the following publications: (PMID: 20556798) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 01, 2018

- -

LAMB2-related infantile-onset nephrotic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 2018

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over