3-49121330-C-T

Position:

chr3-49121330-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002292.4(LAMB2):c.5293G>A(p.Ala1765Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,613,976 control chromosomes in the GnomAD database, including 663 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 38 hom., cov: 33)

Exomes 𝑓: 0.027 ( 625 hom. )

Consequence

LAMB2
NM_002292.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.990

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=0.003806591).

BP6

Variant 3-49121330-C-T is Benign according to our data. Variant chr3-49121330-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49121330-C-T is described in Lovd as [Likely_benign]. Variant chr3-49121330-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0191 (2915/152314) while in subpopulation NFE AF= 0.0288 (1962/68026). AF 95% confidence interval is 0.0278. There are 38 homozygotes in gnomad4. There are 1409 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB2	NM_002292.4 link	c.5293G>A	p.Ala1765Thr	missense_variant	32/32	ENST00000305544.9	NP_002283.3	P55268
LAMB2	XM_005265127.5 link	c.5293G>A	p.Ala1765Thr	missense_variant	33/33		XP_005265184.1	P55268

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB2	ENST00000305544.9 link	c.5293G>A	p.Ala1765Thr	missense_variant	32/32	1	NM_002292.4	ENSP00000307156.4		P55268

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2918

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00562

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.0207

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0289

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.0207

AC:

5204

AN:

251462

Hom.:

AF XY:

0.0213

AC XY:

2899

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00468

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0132

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0304

Gnomad OTH exome

AF:

0.0221

GnomAD4 exome

AF:

0.0274

AC:

40078

AN:

1461662

Hom.:

625

Cov.:

AF XY:

0.0271

AC XY:

19717

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00439

Gnomad4 AMR exome

AF:

0.0156

Gnomad4 ASJ exome

AF:

0.0163

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0126

Gnomad4 FIN exome

AF:

0.0202

Gnomad4 NFE exome

AF:

0.0315

Gnomad4 OTH exome

AF:

0.0243

GnomAD4 genome

AF:

0.0191

AC:

2915

AN:

152314

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

1409

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00561

Gnomad4 AMR

AF:

0.0218

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00829

Gnomad4 FIN

AF:

0.0207

Gnomad4 NFE

AF:

0.0288

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0274

Hom.:

114

Bravo

AF:

0.0191

TwinsUK

AF:

0.0375

AC:

139

ALSPAC

AF:

0.0301

AC:

116

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0297

AC:

255

ExAC

AF:

0.0216

AC:

2623

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0315

EpiControl

AF:

0.0312

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2024	See Variant Classification Assertion Criteria. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 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. -

Focal segmental glomerulosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

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

0.070

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.056

T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.84

.;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.66

N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.41

N;N

REVEL

Benign

0.046

Sift

Benign

0.54

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.039

B;B

Vest4

0.041

MPC

0.74

ClinPred

0.0081

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.065

gMVP

0.082

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