3-49123113-C-T

Variant names:

• chr3-49123113-C-T
• rs114913744
• NM_002292.4:c.4224+19G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002292.4(LAMB2):​c.4224+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,609,368 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (14 hom., cov: 33)
  • Exomes 𝑓: 0.012 (240 hom.)
• Consequence: LAMB2 NM_002292.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.531
• Publications: 5 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, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet
• LAMB2-related infantile-onset nephrotic syndrome

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-49123113-C-T is Benign according to our data. Variant chr3-49123113-C-T is described in ClinVar as Benign. ClinVar VariationId is 258611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00706 (1076/152330) while in subpopulation SAS AF = 0.0413 (199/4824). AF 95% confidence interval is 0.0366. There are 14 homozygotes in GnomAd4. There are 565 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.4224+19G>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.4224+19G>A		intron	N/A	ENSP00000307156.4
	LAMB2	ENST00000418109.5	TSL:1	c.4224+19G>A		intron	N/A	ENSP00000388325.1
	LAMB2	ENST00000960189.1		c.4266+19G>A		intron	N/A	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 1080 AN: 152212 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00960

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.0115 AC: 2856 AN: 248064 AF XY: 0.0142

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00330

Gnomad NFE exome AF: 0.00868

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0121 AC: 17665 AN: 1457038 Hom.: 240 Cov.: 34 AF XY: 0.0135 AC XY: 9803 AN XY: 725086

African (AFR) AF: 0.00114 AC: 38 AN: 33478

American (AMR) AF: 0.00438 AC: 196 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0510 AC: 4403 AN: 86258

European-Finnish (FIN) AF: 0.00284 AC: 138 AN: 48638

Middle Eastern (MID) AF: 0.0260 AC: 150 AN: 5768

European-Non Finnish (NFE) AF: 0.0107 AC: 11953 AN: 1111984

Other (OTH) AF: 0.0126 AC: 763 AN: 60358

GnomAD4 genome AF: 0.00706 AC: 1076 AN: 152330 Hom.: 14 Cov.: 33 AF XY: 0.00758 AC XY: 565 AN XY: 74492

African (AFR) AF: 0.00197 AC: 82 AN: 41576

American (AMR) AF: 0.00640 AC: 98 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0413 AC: 199 AN: 4824

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00958 AC: 652 AN: 68028

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00401 Hom.: 1

Bravo AF: 0.00622

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Pierson syndrome;C3280113:LAMB2-related infantile-onset nephrotic syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	10
DANN	Benign	0.46
PhyloP100		0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs114913744; hg19: chr3-49160546;