rs138540017

Variant names:

• chr3-49123943-G-A
• rs138540017
• NM_002292.4:c.3582C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_002292.4(LAMB2):​c.3582C>T​(p.Phe1194Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,382 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: LAMB2 NM_002292.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.66
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 3-49123943-G-A is Benign according to our data. Variant chr3-49123943-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 345986.
• BP7: Synonymous conserved (PhyloP=-1.66 with no splicing effect.

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.3582C>T	p.Phe1194Phe	synonymous	Exon 24 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.3582C>T	p.Phe1194Phe	synonymous	Exon 24 of 32	ENSP00000307156.4	P55268
	LAMB2	ENST00000418109.5	TSL:1	c.3582C>T	p.Phe1194Phe	synonymous	Exon 25 of 33	ENSP00000388325.1	P55268
	LAMB2	ENST00000960189.1		c.3624C>T	p.Phe1208Phe	synonymous	Exon 24 of 32	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000706 AC: 176 AN: 249314 AF XY: 0.000793

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.00112 AC: 1642 AN: 1461054 Hom.: 1 Cov.: 34 AF XY: 0.00115 AC XY: 835 AN XY: 726816

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.000313 AC: 14 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000985 AC: 85 AN: 86258

European-Finnish (FIN) AF: 0.0000570 AC: 3 AN: 52606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00134 AC: 1486 AN: 1112002

Other (OTH) AF: 0.000679 AC: 41 AN: 60390

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74496

African (AFR) AF: 0.000265 AC: 11 AN: 41580

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000815 Hom.: 0

Bravo AF: 0.000654

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	LAMB2-related infantile-onset nephrotic syndrome (1)
-	-	1	not provided (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	-0.48
CADD	Benign	0.72
DANN	Benign	0.84
PhyloP100		-1.7
Mutation Taster		=96/4	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: rs138540017; hg19: chr3-49161376; COSMIC: COSV100025963; COSMIC: COSV100025963;