3-49129027-C-T

Variant names:

• chr3-49129027-C-T
• rs61729152
• NM_002292.4:c.1724G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002292.4(LAMB2):​c.1724G>A​(p.Arg575Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,609,380 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (26 hom., cov: 33)
  • Exomes 𝑓: 0.018 (307 hom.)
• Consequence: LAMB2 NM_002292.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.28
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038977563).
• BP6: Variant 3-49129027-C-T is Benign according to our data. Variant chr3-49129027-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0128 (1944/152320) while in subpopulation NFE AF = 0.0196 (1335/68014). AF 95% confidence interval is 0.0188. There are 26 homozygotes in GnomAd4. There are 958 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB2	NM_002292.4	MANE Select	c.1724G>A	p.Arg575Gln	missense	Exon 13 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.1724G>A	p.Arg575Gln	missense	Exon 13 of 32	ENSP00000307156.4	P55268
	LAMB2	ENST00000418109.5	TSL:1	c.1724G>A	p.Arg575Gln	missense	Exon 14 of 33	ENSP00000388325.1	P55268
	LAMB2	ENST00000960189.1		c.1724G>A	p.Arg575Gln	missense	Exon 13 of 32	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1945 AN: 152202 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0113 AC: 2790 AN: 246610 AF XY: 0.0111

Gnomad AFR exome AF: 0.00380

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0191

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.00970

GnomAD4 exome AF: 0.0182 AC: 26498 AN: 1457060 Hom.: 307 Cov.: 35 AF XY: 0.0175 AC XY: 12708 AN XY: 724990

African (AFR) AF: 0.00275 AC: 92 AN: 33480

American (AMR) AF: 0.00552 AC: 247 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26136

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

South Asian (SAS) AF: 0.00122 AC: 105 AN: 86258

European-Finnish (FIN) AF: 0.0204 AC: 995 AN: 48656

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0219 AC: 24336 AN: 1111974

Other (OTH) AF: 0.0114 AC: 687 AN: 60368

GnomAD4 genome AF: 0.0128 AC: 1944 AN: 152320 Hom.: 26 Cov.: 33 AF XY: 0.0129 AC XY: 958 AN XY: 74484

African (AFR) AF: 0.00404 AC: 168 AN: 41574

American (AMR) AF: 0.0103 AC: 157 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0196 AC: 1335 AN: 68014

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.0166 Hom.: 71

Bravo AF: 0.0118

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0162 AC: 139

ExAC AF: 0.0114 AC: 1383

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0173

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (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
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.92
DANN	Benign	0.80
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.3
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.026
Sift	Benign	0.22	T
Sift4G	Benign	0.46	T
Polyphen		0.0020	B
Vest4		0.086
MPC		0.53
ClinPred		0.000058	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.021
gMVP		0.41
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61729152; hg19: chr3-49166460; COSMIC: COSV107369144; COSMIC: COSV107369144;