rs11550620

Variant names:

• chr3-49121244-G-C
• rs11550620
• NM_002292.4:c.5379C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-49121244-G-C
• chr3-49121244-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002292.4(LAMB2):​c.5379C>G​(p.Ile1793Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,612,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: LAMB2 NM_002292.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.93
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16025978).

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.5379C>G	p.Ile1793Met	missense	Exon 32 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.5379C>G	p.Ile1793Met	missense	Exon 32 of 32	ENSP00000307156.4	P55268
	LAMB2	ENST00000418109.5	TSL:1	c.5379C>G	p.Ile1793Met	missense	Exon 33 of 33	ENSP00000388325.1	P55268
	LAMB2	ENST00000960189.1		c.5421C>G	p.Ile1807Met	missense	Exon 32 of 32	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251198 AF XY: 0.000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000216 AC: 316 AN: 1459932 Hom.: 0 Cov.: 32 AF XY: 0.000191 AC XY: 139 AN XY: 726264

African (AFR) AF: 0.0000599 AC: 2 AN: 33414

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53364

Middle Eastern (MID) AF: 0.000238 AC: 1 AN: 4198

European-Non Finnish (NFE) AF: 0.000255 AC: 284 AN: 1111998

Other (OTH) AF: 0.000183 AC: 11 AN: 60228

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74360

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.000458 AC: 7 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000220 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Benign	0.059	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.43
MVP		0.33
MPC		1.8
ClinPred		0.19	T
GERP RS		3.5
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.26
Mutation Taster		=60/40	polymorphism

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: rs11550620; hg19: chr3-49158677;