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rs34290943

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002292.4(LAMB2):ā€‹c.3387A>Gā€‹(p.Gln1129=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,614,016 control chromosomes in the GnomAD database, including 12,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.092 ( 931 hom., cov: 33)
Exomes š‘“: 0.12 ( 11562 hom. )

Consequence

LAMB2
NM_002292.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.789
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-49124227-T-C is Benign according to our data. Variant chr3-49124227-T-C is described in ClinVar as [Benign]. Clinvar id is 258608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49124227-T-C is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.789 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LAMB2NM_002292.4 linkuse as main transcriptc.3387A>G p.Gln1129= synonymous_variant 23/32 ENST00000305544.9
LAMB2XM_005265127.5 linkuse as main transcriptc.3387A>G p.Gln1129= synonymous_variant 24/33

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LAMB2ENST00000305544.9 linkuse as main transcriptc.3387A>G p.Gln1129= synonymous_variant 23/321 NM_002292.4 P1
LAMB2ENST00000418109.5 linkuse as main transcriptc.3387A>G p.Gln1129= synonymous_variant 24/331 P1
LAMB2ENST00000480640.1 linkuse as main transcriptn.145A>G non_coding_transcript_exon_variant 2/33
LAMB2ENST00000538659.1 linkuse as main transcriptn.397A>G non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0920
AC:
13994
AN:
152154
Hom.:
930
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0191
Gnomad AMI
AF:
0.0570
Gnomad AMR
AF:
0.0670
Gnomad ASJ
AF:
0.234
Gnomad EAS
AF:
0.00309
Gnomad SAS
AF:
0.145
Gnomad FIN
AF:
0.188
Gnomad MID
AF:
0.136
Gnomad NFE
AF:
0.123
Gnomad OTH
AF:
0.0788
GnomAD3 exomes
AF:
0.109
AC:
27299
AN:
251184
Hom.:
1963
AF XY:
0.115
AC XY:
15663
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.0171
Gnomad AMR exome
AF:
0.0512
Gnomad ASJ exome
AF:
0.235
Gnomad EAS exome
AF:
0.00125
Gnomad SAS exome
AF:
0.154
Gnomad FIN exome
AF:
0.181
Gnomad NFE exome
AF:
0.119
Gnomad OTH exome
AF:
0.118
GnomAD4 exome
AF:
0.118
AC:
172833
AN:
1461744
Hom.:
11562
Cov.:
36
AF XY:
0.120
AC XY:
87401
AN XY:
727178
show subpopulations
Gnomad4 AFR exome
AF:
0.0162
Gnomad4 AMR exome
AF:
0.0518
Gnomad4 ASJ exome
AF:
0.234
Gnomad4 EAS exome
AF:
0.00118
Gnomad4 SAS exome
AF:
0.158
Gnomad4 FIN exome
AF:
0.170
Gnomad4 NFE exome
AF:
0.120
Gnomad4 OTH exome
AF:
0.121
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0919
AC:
13992
AN:
152272
Hom.:
931
Cov.:
33
AF XY:
0.0953
AC XY:
7092
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.0190
Gnomad4 AMR
AF:
0.0669
Gnomad4 ASJ
AF:
0.234
Gnomad4 EAS
AF:
0.00309
Gnomad4 SAS
AF:
0.145
Gnomad4 FIN
AF:
0.188
Gnomad4 NFE
AF:
0.123
Gnomad4 OTH
AF:
0.0784
Alfa
AF:
0.119
Hom.:
557
Bravo
AF:
0.0760
Asia WGS
AF:
0.0610
AC:
217
AN:
3478
EpiCase
AF:
0.124
EpiControl
AF:
0.116

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Pierson syndrome;C3280113:LAMB2-related infantile-onset nephrotic syndrome Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxFeb 01, 2020- -
LAMB2-related infantile-onset nephrotic syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.60
CADD
Benign
3.0
DANN
Benign
0.56
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs34290943; hg19: chr3-49161660; API