rs35713889

Variant names:

• chr3-49125150-C-T
• rs35713889
• NM_002292.4:c.2740G>A
• LAMB2 p.Gly914Arg

Your query was ambiguous. Multiple possible variants found:

• chr3-49125150-C-T
• chr3-49125150-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002292.4(LAMB2):​c.2740G>A​(p.Gly914Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,613,490 control chromosomes in the GnomAD database, including 1,330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (107 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1223 hom.)
• Consequence: LAMB2 NM_002292.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.78
• Publications: 25 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: Orphanet, G2P
• 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 (MetaRNN=0.0073587894).
• BP6: Variant 3-49125150-C-T is Benign according to our data. Variant chr3-49125150-C-T is described in ClinVar as Benign. ClinVar VariationId is 258605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

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.2740G>A	p.Gly914Arg	missense	Exon 20 of 32	NP_002283.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB2	ENST00000305544.9	TSL:1 MANE Select	c.2740G>A	p.Gly914Arg	missense	Exon 20 of 32	ENSP00000307156.4	P55268
	LAMB2	ENST00000418109.5	TSL:1	c.2740G>A	p.Gly914Arg	missense	Exon 21 of 33	ENSP00000388325.1	P55268
	LAMB2	ENST00000960189.1		c.2782G>A	p.Gly928Arg	missense	Exon 20 of 32	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5412 AN: 152170 Hom.: 107 Cov.: 33

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0472

Gnomad EAS AF: 0.00924

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0390

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0320 AC: 7998 AN: 249630 AF XY: 0.0323

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0448

Gnomad EAS exome AF: 0.00495

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0388

GnomAD4 exome AF: 0.0396 AC: 57849 AN: 1461202 Hom.: 1223 Cov.: 36 AF XY: 0.0391 AC XY: 28423 AN XY: 726904

African (AFR) AF: 0.0405 AC: 1356 AN: 33480

American (AMR) AF: 0.0219 AC: 981 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0437 AC: 1143 AN: 26136

East Asian (EAS) AF: 0.00247 AC: 98 AN: 39696

South Asian (SAS) AF: 0.0257 AC: 2219 AN: 86256

European-Finnish (FIN) AF: 0.0230 AC: 1216 AN: 52876

Middle Eastern (MID) AF: 0.0655 AC: 378 AN: 5768

European-Non Finnish (NFE) AF: 0.0431 AC: 47947 AN: 1111896

Other (OTH) AF: 0.0416 AC: 2511 AN: 60372

GnomAD4 genome AF: 0.0356 AC: 5415 AN: 152288 Hom.: 107 Cov.: 33 AF XY: 0.0352 AC XY: 2623 AN XY: 74468

African (AFR) AF: 0.0405 AC: 1685 AN: 41558

American (AMR) AF: 0.0269 AC: 412 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 164 AN: 3472

East Asian (EAS) AF: 0.00907 AC: 47 AN: 5184

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4828

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10616

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0390 AC: 2651 AN: 68008

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0392 Hom.: 427

Bravo AF: 0.0365

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.0395

EpiControl AF: 0.0404

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	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
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.42
Sift	Benign	0.056	T
Sift4G	Uncertain	0.052	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.71
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35713889;

hg19: chr3-49162583;