3-49125150-C-T

Position:

chr3-49125150-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.2740G>A(p.Gly914Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,613,490 control chromosomes in the GnomAD database, including 1,330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 107 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1223 hom. )

Consequence

LAMB2
NM_002292.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.78

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=0.0073587894).

BP6

Variant 3-49125150-C-T is Benign according to our data. Variant chr3-49125150-C-T is described in ClinVar as [Benign]. Clinvar id is 258605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49125150-C-T is described in Lovd as [Benign]. Variant chr3-49125150-C-T is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB2	NM_002292.4 linkuse as main transcript	c.2740G>A	p.Gly914Arg	missense_variant	20/32	ENST00000305544.9	NP_002283.3
LAMB2	XM_005265127.5 linkuse as main transcript	c.2740G>A	p.Gly914Arg	missense_variant	21/33		XP_005265184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB2	ENST00000305544.9 linkuse as main transcript	c.2740G>A	p.Gly914Arg	missense_variant	20/32	1	NM_002292.4	ENSP00000307156	P1

Frequencies

GnomAD3 genomes

AF:

0.0356

AC:

5412

AN:

152170

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0405

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0270

Gnomad ASJ

AF:

0.0472

Gnomad EAS

AF:

0.00924

Gnomad SAS

AF:

0.0281

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0390

Gnomad OTH

AF:

0.0330

GnomAD3 exomes

AF:

0.0320

AC:

7998

AN:

249630

Hom.:

152

AF XY:

0.0323

AC XY:

4361

AN XY:

135102

show subpopulations

Gnomad AFR exome

AF:

0.0401

Gnomad AMR exome

AF:

0.0213

Gnomad ASJ exome

AF:

0.0448

Gnomad EAS exome

AF:

0.00495

Gnomad SAS exome

AF:

0.0256

Gnomad FIN exome

AF:

0.0223

Gnomad NFE exome

AF:

0.0408

Gnomad OTH exome

AF:

0.0388

GnomAD4 exome

AF:

0.0396

AC:

57849

AN:

1461202

Hom.:

1223

Cov.:

AF XY:

0.0391

AC XY:

28423

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.0405

Gnomad4 AMR exome

AF:

0.0219

Gnomad4 ASJ exome

AF:

0.0437

Gnomad4 EAS exome

AF:

0.00247

Gnomad4 SAS exome

AF:

0.0257

Gnomad4 FIN exome

AF:

0.0230

Gnomad4 NFE exome

AF:

0.0431

Gnomad4 OTH exome

AF:

0.0416

GnomAD4 genome

AF:

0.0356

AC:

5415

AN:

152288

Hom.:

107

Cov.:

AF XY:

0.0352

AC XY:

2623

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0405

Gnomad4 AMR

AF:

0.0269

Gnomad4 ASJ

AF:

0.0472

Gnomad4 EAS

AF:

0.00907

Gnomad4 SAS

AF:

0.0280

Gnomad4 FIN

AF:

0.0221

Gnomad4 NFE

AF:

0.0390

Gnomad4 OTH

AF:

0.0326

Alfa

AF:

0.0400

Hom.:

220

Bravo

AF:

0.0365

TwinsUK

AF:

0.0458

AC:

170

ALSPAC

AF:

0.0470

AC:

181

ESP6500AA

AF:

0.0384

AC:

169

ESP6500EA

AF:

0.0427

AC:

367

ExAC

AF:

0.0331

AC:

4015

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0395

EpiControl

AF:

0.0404

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2020	This variant is associated with the following publications: (PMID: 26239645, 28146470) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2017	- -
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

Dec 08, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

Uncertain

0.44

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.80

.;T

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Uncertain

0.42

Sift

Benign

0.056

T;T

Sift4G

Uncertain

0.052

T;T

Polyphen

1.0

D;D

Vest4

0.71

MutPred

0.77

Loss of catalytic residue at G914 (P = 0.0905);Loss of catalytic residue at G914 (P = 0.0905);

MPC

0.75

ClinPred

0.035

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.52

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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