rs79448908

Variant names:

• chr3-49132349-G-A
• rs79448908
• NM_002292.4:c.306C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-49132349-G-A
• chr3-49132349-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002292.4(LAMB2):​c.306C>T​(p.Asn102Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,614,224 control chromosomes in the GnomAD database, including 626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (52 hom., cov: 32)
  • Exomes 𝑓: 0.026 (574 hom.)
• Consequence: LAMB2 NM_002292.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.30
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-49132349-G-A is Benign according to our data. Variant chr3-49132349-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0198 (3010/152344) while in subpopulation NFE AF = 0.0301 (2047/68026). AF 95% confidence interval is 0.029. There are 52 homozygotes in GnomAd4. There are 1432 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB2	NM_002292.4	MANE Select	c.306C>T	p.Asn102Asn	synonymous	Exon 3 of 32	NP_002283.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB2	ENST00000305544.9	TSL:1 MANE Select	c.306C>T	p.Asn102Asn	synonymous	Exon 3 of 32	ENSP00000307156.4
	LAMB2	ENST00000418109.5	TSL:1	c.306C>T	p.Asn102Asn	synonymous	Exon 4 of 33	ENSP00000388325.1
	LAMB2	ENST00000494831.1	TSL:2	c.-27-195C>T		intron	N/A	ENSP00000444751.1

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3010 AN: 152226 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.00470

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0301

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0221 AC: 5546 AN: 251474 AF XY: 0.0224

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0331

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0259 AC: 37870 AN: 1461880 Hom.: 574 Cov.: 32 AF XY: 0.0255 AC XY: 18533 AN XY: 727244

African (AFR) AF: 0.00469 AC: 157 AN: 33480

American (AMR) AF: 0.0140 AC: 625 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 696 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00769 AC: 663 AN: 86258

European-Finnish (FIN) AF: 0.0313 AC: 1671 AN: 53418

Middle Eastern (MID) AF: 0.0484 AC: 279 AN: 5768

European-Non Finnish (NFE) AF: 0.0290 AC: 32232 AN: 1112000

Other (OTH) AF: 0.0256 AC: 1546 AN: 60396

GnomAD4 genome AF: 0.0198 AC: 3010 AN: 152344 Hom.: 52 Cov.: 32 AF XY: 0.0192 AC XY: 1432 AN XY: 74496

African (AFR) AF: 0.00474 AC: 197 AN: 41586

American (AMR) AF: 0.0200 AC: 306 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3472

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

South Asian (SAS) AF: 0.00600 AC: 29 AN: 4834

European-Finnish (FIN) AF: 0.0256 AC: 272 AN: 10616

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0301 AC: 2047 AN: 68026

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0261 Hom.: 47

Bravo AF: 0.0191

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Kidney disorder (1)
-	-	1	LAMB2-related infantile-onset nephrotic syndrome (1)
-	-	1	Pierson syndrome (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	-0.61
CADD	Benign	8.8
DANN	Benign	0.93
PhyloP100		1.3
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: rs79448908; hg19: chr3-49169782;