NM_002292.4:c.1193C>T

Variant names:

Variant summary

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

The NM_002292.4(LAMB2):c.1193C>T(p.Thr398Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,238 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 18 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 11 hom. )

Consequence

LAMB2
NM_002292.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.36

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=0.0070331097).

BP6

Variant 3-49130263-G-A is Benign according to our data. Variant chr3-49130263-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49130263-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00719 (1095/152366) while in subpopulation AFR AF= 0.0254 (1056/41582). AF 95% confidence interval is 0.0241. There are 18 homozygotes in gnomad4. There are 527 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB2	NM_002292.4 link	c.1193C>T	p.Thr398Ile	missense_variant	Exon 9 of 32	ENST00000305544.9	NP_002283.3	P55268
LAMB2	XM_005265127.5 link	c.1193C>T	p.Thr398Ile	missense_variant	Exon 10 of 33		XP_005265184.1	P55268

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMB2	ENST00000305544.9 link	c.1193C>T	p.Thr398Ile	missense_variant	Exon 9 of 32	1	NM_002292.4	ENSP00000307156.4		P55268
LAMB2	ENST00000418109.5 link	c.1193C>T	p.Thr398Ile	missense_variant	Exon 10 of 33	1		ENSP00000388325.1		P55268

Frequencies

GnomAD3 genomes

AF:

0.00717

AC:

1092

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00188

AC:

472

AN:

251312

Hom.:

AF XY:

0.00124

AC XY:

168

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0254

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000730

AC:

1067

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

439

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0256

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.00719

AC:

1095

AN:

152366

Hom.:

Cov.:

AF XY:

0.00707

AC XY:

527

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0254

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.00778

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00234

AC:

284

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

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

May 12, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20556798, 30013592) -

Dec 07, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kidney disorder

Benign:1

Feb 13, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LAMB2-related infantile-onset nephrotic syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.39

.;T

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.053

Sift

Benign

0.099

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.053

B;B

Vest4

0.36

MVP

0.33

MPC

0.56

ClinPred

0.0027

GERP RS

-0.089

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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