3-49123193-C-T

Position:

chr3-49123193-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.4163G>A(p.Arg1388Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,613,876 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 14 hom. )

Consequence

LAMB2
NM_002292.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0220

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=0.004136443).

BP6

Variant 3-49123193-C-T is Benign according to our data. Variant chr3-49123193-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 472485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49123193-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00263 (3850/1461580) while in subpopulation NFE AF= 0.00295 (3280/1112008). AF 95% confidence interval is 0.00287. There are 14 homozygotes in gnomad4_exome. There are 1916 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB2	NM_002292.4 linkuse as main transcript	c.4163G>A	p.Arg1388Gln	missense_variant	26/32	ENST00000305544.9
LAMB2	XM_005265127.5 linkuse as main transcript	c.4163G>A	p.Arg1388Gln	missense_variant	27/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LAMB2	ENST00000305544.9 linkuse as main transcript	c.4163G>A	p.Arg1388Gln	missense_variant	26/32	1	NM_002292.4	P1
LAMB2	ENST00000418109.5 linkuse as main transcript	c.4163G>A	p.Arg1388Gln	missense_variant	27/33	1		P1
LAMB2	ENST00000469665.1 linkuse as main transcript	n.393G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00260

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00196

AC:

493

AN:

251428

Hom.:

AF XY:

0.00197

AC XY:

268

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.00430

Gnomad NFE exome

AF:

0.00284

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00263

AC:

3850

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

1916

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00155

Gnomad4 FIN exome

AF:

0.00395

Gnomad4 NFE exome

AF:

0.00295

Gnomad4 OTH exome

AF:

0.00301

GnomAD4 genome

AF:

0.00155

AC:

236

AN:

152296

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.00260

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00254

Hom.:

Bravo

AF:

0.00148

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00206

AC:

250

EpiCase

AF:

0.00333

EpiControl

AF:

0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

LAMB2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

LAMB2: BP4, BS2 -

LAMB2-related infantile-onset nephrotic syndrome

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Pierson syndrome

Benign:1

Likely 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

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.12

DANN

Benign

0.89

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.71

.;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.36

N;N

MutationTaster

Benign

0.95

D;D

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.092

Sift

Benign

0.37

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0040

B;B

Vest4

0.11

MVP

0.20

MPC

0.19

ClinPred

0.00074

GERP RS

-5.5

Varity_R

0.021

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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