rs149653966

Positions:

• chr3-49124865-C-A
• chr3-49124865-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002292.4(LAMB2):​c.2945G>T​(p.Arg982Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R982Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: LAMB2 NM_002292.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.132

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42230704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB2	NM_002292.4	c.2945G>T	p.Arg982Leu	missense_variant	21/32	ENST00000305544.9
LAMB2	XM_005265127.5	c.2945G>T	p.Arg982Leu	missense_variant	22/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB2	ENST00000305544.9	c.2945G>T	p.Arg982Leu	missense_variant	21/32	1	NM_002292.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251380 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461798 Hom.: 0 Cov.: 35 AF XY: 0.0000151 AC XY: 11 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.51	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.24
Sift	Benign	0.40	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.90	P;P
Vest4		0.36
MutPred		0.63		Loss of phosphorylation at S977 (P = 0.1393);Loss of phosphorylation at S977 (P = 0.1393);
MVP		0.52
MPC		0.43
ClinPred		0.52	D
GERP RS		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.30

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

Other links and lift over

dbSNP: rs149653966; hg19: chr3-49162298;