rs144092322

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_002292.4(LAMB2):c.2673C>T(p.Gly891=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,910 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 6 hom., cov: 33)

Exomes 𝑓: 0.011 ( 123 hom. )

Consequence

LAMB2
NM_002292.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0150

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 3-49125300-G-A is Benign according to our data. Variant chr3-49125300-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49125300-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00754 (1149/152334) while in subpopulation NFE AF= 0.0111 (758/68032). AF 95% confidence interval is 0.0105. There are 6 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB2	NM_002292.4 linkuse as main transcript	c.2673C>T	p.Gly891=	synonymous_variant	19/32	ENST00000305544.9
LAMB2	XM_005265127.5 linkuse as main transcript	c.2673C>T	p.Gly891=	synonymous_variant	20/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB2	ENST00000305544.9 linkuse as main transcript	c.2673C>T	p.Gly891=	synonymous_variant	19/32	1	NM_002292.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00756

AC:

1150

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00811

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.00395

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00866

AC:

2176

AN:

251252

Hom.:

AF XY:

0.00933

AC XY:

1267

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00760

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00621

Gnomad FIN exome

AF:

0.00485

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0109

AC:

15996

AN:

1461576

Hom.:

123

Cov.:

AF XY:

0.0109

AC XY:

7890

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.00818

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00645

Gnomad4 FIN exome

AF:

0.00540

Gnomad4 NFE exome

AF:

0.0118

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.00754

AC:

1149

AN:

152334

Hom.:

Cov.:

AF XY:

0.00733

AC XY:

546

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00240

Gnomad4 AMR

AF:

0.00810

Gnomad4 ASJ

AF:

0.0182

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00725

Gnomad4 FIN

AF:

0.00395

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00815

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	This variant is associated with the following publications: (PMID: 20556798) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	LAMB2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2018	- -

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

Invitae

Jan 29, 2024

- -

Focal segmental glomerulosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 06, 2021

- -

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

Cadd

Benign

Dann

Benign

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.34

Position offset: 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