3-49128636-C-T

Variant names:

• chr3-49128636-C-T
• rs9865051
• NM_002292.4:c.1890+25G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002292.4(LAMB2):​c.1890+25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,614,066 control chromosomes in the GnomAD database, including 521,720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (52017 hom., cov: 34)
  • Exomes 𝑓: 0.80 (469703 hom.)
• Consequence: LAMB2 NM_002292.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.08
• Publications: 22 publications found

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: G2P, Orphanet
• LAMB2-related infantile-onset nephrotic syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-49128636-C-T is Benign according to our data. Variant chr3-49128636-C-T is described in ClinVar as Benign. ClinVar VariationId is 1248793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.1890+25G>A		intron	N/A	NP_002283.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB2	ENST00000305544.9	TSL:1 MANE Select	c.1890+25G>A		intron	N/A	ENSP00000307156.4	P55268
	LAMB2	ENST00000418109.5	TSL:1	c.1890+25G>A		intron	N/A	ENSP00000388325.1	P55268
	LAMB2	ENST00000960189.1		c.1890+25G>A		intron	N/A	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125378 AN: 152120 Hom.: 51976 Cov.: 34

Gnomad AFR AF: 0.880

Gnomad AMI AF: 0.737

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.941

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.764

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.795

GnomAD2 exomes AF: 0.839 AC: 210804 AN: 251346 AF XY: 0.837

Gnomad AFR exome AF: 0.878

Gnomad AMR exome AF: 0.900

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.829

Gnomad NFE exome AF: 0.765

Gnomad OTH exome AF: 0.812

GnomAD4 exome AF: 0.799 AC: 1168295 AN: 1461826 Hom.: 469703 Cov.: 70 AF XY: 0.802 AC XY: 583431 AN XY: 727204

African (AFR) AF: 0.882 AC: 29516 AN: 33480

American (AMR) AF: 0.894 AC: 39986 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 21886 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39692 AN: 39700

South Asian (SAS) AF: 0.937 AC: 80845 AN: 86258

European-Finnish (FIN) AF: 0.819 AC: 43741 AN: 53378

Middle Eastern (MID) AF: 0.785 AC: 4530 AN: 5768

European-Non Finnish (NFE) AF: 0.772 AC: 858913 AN: 1111988

Other (OTH) AF: 0.814 AC: 49186 AN: 60394

GnomAD4 genome AF: 0.824 AC: 125478 AN: 152240 Hom.: 52017 Cov.: 34 AF XY: 0.830 AC XY: 61805 AN XY: 74442

African (AFR) AF: 0.880 AC: 36564 AN: 41550

American (AMR) AF: 0.846 AC: 12933 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2930 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5172 AN: 5178

South Asian (SAS) AF: 0.941 AC: 4539 AN: 4826

European-Finnish (FIN) AF: 0.831 AC: 8821 AN: 10616

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51938 AN: 67984

Other (OTH) AF: 0.798 AC: 1688 AN: 2116

Alfa AF: 0.805 Hom.: 9109

Bravo AF: 0.828

Asia WGS AF: 0.961 AC: 3342 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Pierson syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.1
DANN	Benign	0.50
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9865051; hg19: chr3-49166069;