rs34759087

Positions:

chr3-49124851-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002292.4(LAMB2):c.2959G>A(p.Glu987Lys) variant causes a missense change. The variant allele was found at a frequency of 0.116 in 1,614,066 control chromosomes in the GnomAD database, including 12,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E987D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.092 ( 935 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11561 hom. )

Consequence

LAMB2
NM_002292.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.06

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003787607).

BP6

Variant 3-49124851-C-T is Benign according to our data. Variant chr3-49124851-C-T is described in ClinVar as [Benign]. Clinvar id is 258606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49124851-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB2	NM_002292.4 linkuse as main transcript	c.2959G>A	p.Glu987Lys	missense_variant	21/32	ENST00000305544.9
LAMB2	XM_005265127.5 linkuse as main transcript	c.2959G>A	p.Glu987Lys	missense_variant	22/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB2	ENST00000305544.9 linkuse as main transcript	c.2959G>A	p.Glu987Lys	missense_variant	21/32	1	NM_002292.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0921

AC:

14015

AN:

152146

Hom.:

934

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0196

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0668

Gnomad ASJ

AF:

0.234

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.144

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.0794

GnomAD3 exomes

AF:

0.109

AC:

27313

AN:

251384

Hom.:

1963

AF XY:

0.115

AC XY:

15656

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0178

Gnomad AMR exome

AF:

0.0511

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:

0.119

GnomAD4 exome

AF:

0.118

AC:

172908

AN:

1461802

Hom.:

11561

Cov.:

AF XY:

0.120

AC XY:

87413

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0180

Gnomad4 AMR exome

AF:

0.0518

Gnomad4 ASJ exome

AF:

0.233

Gnomad4 EAS exome

AF:

0.00113

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:

0.0920

AC:

14013

AN:

152264

Hom.:

935

Cov.:

AF XY:

0.0954

AC XY:

7101

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0196

Gnomad4 AMR

AF:

0.0667

Gnomad4 ASJ

AF:

0.234

Gnomad4 EAS

AF:

0.00309

Gnomad4 SAS

AF:

0.145

Gnomad4 FIN

AF:

0.188

Gnomad4 NFE

AF:

0.124

Gnomad4 OTH

AF:

0.0791

Alfa

AF:

0.117

Hom.:

2511

Bravo

AF:

0.0761

TwinsUK

AF:

0.119

AC:

442

ALSPAC

AF:

0.118

AC:

456

ESP6500AA

AF:

0.0207

AC:

ESP6500EA

AF:

0.132

AC:

1139

ExAC

AF:

0.106

AC:

12816

Asia WGS

AF:

0.0620

AC:

221

AN:

3478

EpiCase

AF:

0.124

EpiControl

AF:

0.116

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2020

- -

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

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

.;D

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.083

Sift

Uncertain

0.024

D;D

Sift4G

Uncertain

0.049

D;D

Polyphen

0.70

P;P

Vest4

0.18

MPC

0.19

ClinPred

0.0067

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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