rs116836607

Variant names:

• chr3-49121927-T-C
• rs116836607
• NM_002292.4:c.4923+17A>G

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.4923+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,613,822 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 33)
  • Exomes 𝑓: 0.022 (412 hom.)
• Consequence: LAMB2 NM_002292.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.32
• Publications: 6 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=-0.6).
• BP6: Variant 3-49121927-T-C is Benign according to our data. Variant chr3-49121927-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258614.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 = 0.0154 (2341/152264) while in subpopulation NFE AF = 0.023 (1565/67996). AF 95% confidence interval is 0.0221. There are 24 homozygotes in GnomAd4. There are 1133 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.4923+17A>G		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.4923+17A>G		intron	N/A	ENSP00000307156.4	P55268
	LAMB2	ENST00000418109.5	TSL:1	c.4923+17A>G		intron	N/A	ENSP00000388325.1	P55268
	LAMB2	ENST00000960189.1		c.4965+17A>G		intron	N/A	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2344 AN: 152146 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00447

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0164 AC: 4121 AN: 251242 AF XY: 0.0165

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0225 AC: 32839 AN: 1461558 Hom.: 412 Cov.: 33 AF XY: 0.0220 AC XY: 15997 AN XY: 727098

African (AFR) AF: 0.00361 AC: 121 AN: 33478

American (AMR) AF: 0.0121 AC: 539 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 322 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00534 AC: 461 AN: 86258

European-Finnish (FIN) AF: 0.0193 AC: 1026 AN: 53104

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.0261 AC: 29071 AN: 1112000

Other (OTH) AF: 0.0202 AC: 1221 AN: 60394

GnomAD4 genome AF: 0.0154 AC: 2341 AN: 152264 Hom.: 24 Cov.: 33 AF XY: 0.0152 AC XY: 1133 AN XY: 74462

African (AFR) AF: 0.00445 AC: 185 AN: 41550

American (AMR) AF: 0.0173 AC: 264 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.0200 AC: 212 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0230 AC: 1565 AN: 67996

Other (OTH) AF: 0.0157 AC: 33 AN: 2108

Alfa AF: 0.0178 Hom.: 6

Bravo AF: 0.0154

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.6
DANN	Benign	0.75
PhyloP100		-2.3
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: rs116836607; hg19: chr3-49159360;