NM_002292.4:c.4923+17A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002292.4(LAMB2):c.4923+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,613,822 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 33)

Exomes 𝑓: 0.022 ( 412 hom. )

Consequence

LAMB2
NM_002292.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.32

Publications

6 publications found

Variant links:

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)

LAMB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 3-49121927-T-C is Benign according to our data. Variant chr3-49121927-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258614.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 = 0.0154 (2341/152264) while in subpopulation NFE AF = 0.023 (1565/67996). AF 95% confidence interval is 0.0221. There are 24 homozygotes in GnomAd4. There are 1133 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB2	NM_002292.4 link	c.4923+17A>G		intron_variant	Intron 29 of 31	ENST00000305544.9	NP_002283.3	P55268
LAMB2	XM_005265127.5 link	c.4923+17A>G		intron_variant	Intron 30 of 32		XP_005265184.1	P55268

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMB2	ENST00000305544.9 link	c.4923+17A>G	intron_variant	Intron 29 of 31	1	NM_002292.4	ENSP00000307156.4	P55268
LAMB2	ENST00000418109.5 link	c.4923+17A>G	intron_variant	Intron 30 of 32	1		ENSP00000388325.1	P55268
LAMB2	ENST00000467506.5 link	n.33+17A>G	intron_variant	Intron 1 of 2	2
LAMB2	ENST00000498377.1 link	n.578+17A>G	intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2344

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00447

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0173

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0230

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0164

AC:

4121

AN:

251242

AF XY:

0.0165

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0189

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0178

GnomAD4 exome

AF:

0.0225

AC:

32839

AN:

1461558

Hom.:

412

Cov.:

AF XY:

0.0220

AC XY:

15997

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00361

AC:

121

AN:

33478

American (AMR)

AF:

0.0121

AC:

539

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0123

AC:

322

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00534

AC:

461

AN:

86258

European-Finnish (FIN)

AF:

0.0193

AC:

1026

AN:

53104

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0261

AC:

29071

AN:

1112000

Other (OTH)

AF:

0.0202

AC:

1221

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

2196

4393

6589

8786

10982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1094

2188

3282

4376

5470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0154

AC:

2341

AN:

152264

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1133

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00445

AC:

185

AN:

41550

American (AMR)

AF:

0.0173

AC:

264

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00331

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0200

AC:

212

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0230

AC:

1565

AN:

67996

Other (OTH)

AF:

0.0157

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0178

Hom.:

Bravo

AF:

0.0154

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.6

(source)

DANN

Benign

0.75

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over