rs72936885

chr3-49121895-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002292.4(LAMB2):c.4924-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,613,630 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (17 hom.)
• Consequence: LAMB2 NM_002292.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.543

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-49121895-C-T is Benign according to our data. Variant chr3-49121895-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1218980.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-49121895-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00782 (1192/152346) while in subpopulation AFR AF= 0.0227 (944/41572). AF 95% confidence interval is 0.0215. There are 18 homozygotes in gnomad4. There are 553 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB2	NM_002292.4	c.4924-35G>A		intron_variant		ENST00000305544.9
LAMB2	XM_005265127.5	c.4924-35G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB2	ENST00000305544.9	c.4924-35G>A		intron_variant		1	NM_002292.4	P1
LAMB2	ENST00000418109.5	c.4924-35G>A		intron_variant		1		P1
LAMB2	ENST00000467506.5	n.34-35G>A		intron_variant, non_coding_transcript_variant		2
LAMB2	ENST00000498377.1	n.579-35G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00783 AC: 1192 AN: 152228 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00374 AC: 938 AN: 251008 Hom.: 10 AF XY: 0.00323 AC XY: 439 AN XY: 135738

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00258 AC: 3765 AN: 1461284 Hom.: 17 Cov.: 33 AF XY: 0.00242 AC XY: 1756 AN XY: 726972

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00204

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00782 AC: 1192 AN: 152346 Hom.: 18 Cov.: 33 AF XY: 0.00742 AC XY: 553 AN XY: 74510

Gnomad4 AFR AF: 0.0227

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00439 Hom.: 0

Bravo AF: 0.00845

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.8
Dann	Benign	0.61

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: rs72936885; hg19: chr3-49159328;