rs116836607

Positions:

• chr3-49121927-T-C

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: -2.32

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 258614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49121927-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB2	NM_002292.4	c.4923+17A>G		intron_variant		ENST00000305544.9
LAMB2	XM_005265127.5	c.4923+17A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB2	ENST00000305544.9	c.4923+17A>G		intron_variant		1	NM_002292.4	P1
LAMB2	ENST00000418109.5	c.4923+17A>G		intron_variant		1		P1
LAMB2	ENST00000467506.5	n.33+17A>G		intron_variant, non_coding_transcript_variant		2
LAMB2	ENST00000498377.1	n.578+17A>G		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.0164 AC: 4121 AN: 251242 Hom.: 51 AF XY: 0.0165 AC XY: 2242 AN XY: 135822

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 SAS exome AF: 0.00529

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

Gnomad4 AFR exome AF: 0.00361

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00534

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.0261

Gnomad4 OTH exome AF: 0.0202

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

Gnomad4 AFR AF: 0.00445

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0200

Gnomad4 NFE AF: 0.0230

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.0178 Hom.: 6

Bravo AF: 0.0154

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Pierson syndrome;C3280113:LAMB2-related infantile-onset nephrotic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.6
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs116836607; hg19: chr3-49159360;