3-49121330-C-T

Variant names:

• chr3-49121330-C-T
• rs74951356
• NM_002292.4:c.5293G>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.5293G>A​(p.Ala1765Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,613,976 control chromosomes in the GnomAD database, including 663 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (38 hom., cov: 33)
  • Exomes 𝑓: 0.027 (625 hom.)
• Consequence: LAMB2 NM_002292.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.990
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003806591).
• BP6: Variant 3-49121330-C-T is Benign according to our data. Variant chr3-49121330-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258615.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 = 0.0191 (2915/152314) while in subpopulation NFE AF = 0.0288 (1962/68026). AF 95% confidence interval is 0.0278. There are 38 homozygotes in GnomAd4. There are 1409 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 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.5293G>A	p.Ala1765Thr	missense	Exon 32 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.5293G>A	p.Ala1765Thr	missense	Exon 32 of 32	ENSP00000307156.4
	LAMB2	ENST00000418109.5	TSL:1	c.5293G>A	p.Ala1765Thr	missense	Exon 33 of 33	ENSP00000388325.1
	LAMB2	ENST00000467506.5	TSL:2	n.473G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2918 AN: 152196 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0207 AC: 5204 AN: 251462 AF XY: 0.0213

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0274 AC: 40078 AN: 1461662 Hom.: 625 Cov.: 33 AF XY: 0.0271 AC XY: 19717 AN XY: 727146

African (AFR) AF: 0.00439 AC: 147 AN: 33478

American (AMR) AF: 0.0156 AC: 698 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 425 AN: 26136

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

South Asian (SAS) AF: 0.0126 AC: 1086 AN: 86246

European-Finnish (FIN) AF: 0.0202 AC: 1079 AN: 53410

Middle Eastern (MID) AF: 0.0225 AC: 126 AN: 5598

European-Non Finnish (NFE) AF: 0.0315 AC: 35049 AN: 1112006

Other (OTH) AF: 0.0243 AC: 1468 AN: 60364

GnomAD4 genome AF: 0.0191 AC: 2915 AN: 152314 Hom.: 38 Cov.: 33 AF XY: 0.0189 AC XY: 1409 AN XY: 74492

African (AFR) AF: 0.00561 AC: 233 AN: 41562

American (AMR) AF: 0.0218 AC: 333 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

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

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4826

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0288 AC: 1962 AN: 68026

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0265 Hom.: 248

Bravo AF: 0.0191

TwinsUK AF: 0.0375 AC: 139

ALSPAC AF: 0.0301 AC: 116

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0297 AC: 255

ExAC AF: 0.0216 AC: 2623

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0315

EpiControl AF: 0.0312

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 07, 2025

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria.

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pierson syndrome;C3280113:LAMB2-related infantile-onset nephrotic syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LAMB2-related infantile-onset nephrotic syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Focal segmental glomerulosclerosis Benign:1

Jan 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pierson syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.66	N
PhyloP100		0.99
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.046
Sift	Benign	0.54	T
Sift4G	Benign	0.59	T
Polyphen		0.039	B
Vest4		0.041
MPC		0.74
ClinPred		0.0081	T
GERP RS		5.3
PromoterAI		-0.0091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.082
Mutation Taster		=96/4	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: rs74951356; hg19: chr3-49158763; COSMIC: COSV108822030; COSMIC: COSV108822030;