rs74951356

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:8

Conservation

PhyloP100: 0.990

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

Pierson syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
LAMB2-related infantile-onset nephrotic syndrome
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

LAMB2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002292.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 258615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002292.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB2	NM_002292.4	MANE Select	c.5293G>A	p.Ala1765Thr	missense	Exon 32 of 32	NP_002283.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAMB2	ENST00000305544.9	TSL:1 MANE Select	c.5293G>A	p.Ala1765Thr	missense	Exon 32 of 32	ENSP00000307156.4	P55268
LAMB2	ENST00000418109.5	TSL:1	c.5293G>A	p.Ala1765Thr	missense	Exon 33 of 33	ENSP00000388325.1	P55268
LAMB2	ENST00000960189.1		c.5335G>A	p.Ala1779Thr	missense	Exon 32 of 32	ENSP00000630248.1

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

GnomAD2 exomes

AF:

0.0207

AC:

5204

AN:

251462

AF XY:

0.0213

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 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

African (AFR)

AF:

0.00439

AC:

147

AN:

33478

American (AMR)

AF:

0.0156

AC:

698

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

425

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0126

AC:

1086

AN:

86246

European-Finnish (FIN)

AF:

0.0202

AC:

1079

AN:

53410

Middle Eastern (MID)

AF:

0.0225

AC:

126

AN:

5598

European-Non Finnish (NFE)

AF:

0.0315

AC:

35049

AN:

1112006

Other (OTH)

AF:

0.0243

AC:

1468

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2715

5429

8144

10858

13573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1306

2612

3918

5224

6530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0191

AC:

2915

AN:

152314

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

1409

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00561

AC:

233

AN:

41562

American (AMR)

AF:

0.0218

AC:

333

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0207

AC:

220

AN:

10612

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0288

AC:

1962

AN:

68026

Other (OTH)

AF:

0.0208

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

154

308

461

615

769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0265

Hom.:

248

Bravo

AF:

0.0191

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0315

EpiControl

AF:

0.0312

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Focal segmental glomerulosclerosis (1)

LAMB2-related infantile-onset nephrotic syndrome (1)

Pierson syndrome (1)

Pierson syndrome;C3280113:LAMB2-related infantile-onset nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.056

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.66

PhyloP100

0.99

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.41

REVEL

Benign

0.046

Sift

Benign

0.54

Sift4G

Benign

0.59

PromoterAI

-0.0091

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.065

gMVP

0.082

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over