3-49124397-C-T

Variant names:

• chr3-49124397-C-T
• rs79677861
• NM_002292.4:c.3325G>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.3325G>A​(p.Glu1109Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,613,520 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (5 hom.)
• Consequence: LAMB2 NM_002292.4 missense, splice_region
• Scores: Splicing: ADA: 0.01322
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.41
• Publications: 6 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=0.008762777).
• BP6: Variant 3-49124397-C-T is Benign according to our data. Variant chr3-49124397-C-T is described in ClinVar as Benign. ClinVar VariationId is 345988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000492 (75/152366) while in subpopulation EAS AF = 0.0137 (71/5180). AF 95% confidence interval is 0.0111. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.3325G>A	p.Glu1109Lys	missense splice_region	Exon 22 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.3325G>A	p.Glu1109Lys	missense splice_region	Exon 22 of 32	ENSP00000307156.4	P55268
	LAMB2	ENST00000418109.5	TSL:1	c.3325G>A	p.Glu1109Lys	missense splice_region	Exon 23 of 33	ENSP00000388325.1	P55268
	LAMB2	ENST00000960189.1		c.3367G>A	p.Glu1123Lys	missense splice_region	Exon 22 of 32	ENSP00000630248.1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00101 AC: 252 AN: 250468 AF XY: 0.000899

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000270 AC: 394 AN: 1461154 Hom.: 5 Cov.: 35 AF XY: 0.000244 AC XY: 177 AN XY: 726838

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00844 AC: 335 AN: 39696

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53060

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

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111706

Other (OTH) AF: 0.000480 AC: 29 AN: 60372

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74508

African (AFR) AF: 0.0000240 AC: 1 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0137 AC: 71 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000303 Hom.: 0

Bravo AF: 0.000457

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00105 AC: 128

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.14
Sift	Benign	0.060	T
Sift4G	Benign	0.30	T
Polyphen		0.99	D
Vest4		0.45
MVP		0.34
MPC		0.39
ClinPred		0.056	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.46
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.39
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: rs79677861; hg19: chr3-49161830;