2-169213838-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.5859A>G(p.Arg1953Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,613,164 control chromosomes in the GnomAD database, including 9,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1953R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.16 ( 3900 hom., cov: 32)

Exomes 𝑓: 0.061 ( 5384 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.572

Publications

13 publications found

Variant links:

Genes affected

LRP2 (HGNC:6694): (LDL receptor related protein 2) The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

LRP2 Gene-Disease associations (from GenCC):

Donnai-Barrow syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
Stickler syndrome
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P
congenital heart disease
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LRP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 2-169213838-T-C is Benign according to our data. Variant chr2-169213838-T-C is described in ClinVar as Benign. ClinVar VariationId is 129530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.572 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. 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
	LRP2	NM_004525.3	MANE Select	c.5859A>G	p.Arg1953Arg	synonymous	Exon 36 of 79	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.5859A>G	p.Arg1953Arg	synonymous	Exon 36 of 79	ENSP00000496870.1	P98164

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23574

AN:

152056

Hom.:

3894

Cov.:

show subpopulations

Gnomad AFR

AF:

0.420

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0916

Gnomad ASJ

AF:

0.0808

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0412

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0554

Gnomad OTH

AF:

0.127

GnomAD2 exomes

AF:

0.0721

AC:

17968

AN:

249104

AF XY:

0.0658

show subpopulations

Gnomad AFR exome

AF:

0.430

Gnomad AMR exome

AF:

0.0500

Gnomad ASJ exome

AF:

0.0830

Gnomad EAS exome

AF:

0.00136

Gnomad FIN exome

AF:

0.0254

Gnomad NFE exome

AF:

0.0533

Gnomad OTH exome

AF:

0.0673

GnomAD4 exome

AF:

0.0614

AC:

89727

AN:

1460990

Hom.:

5384

Cov.:

AF XY:

0.0603

AC XY:

43813

AN XY:

726816

show subpopulations

African (AFR)

AF:

0.431

AC:

14402

AN:

33386

American (AMR)

AF:

0.0561

AC:

2506

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0783

AC:

2045

AN:

26124

East Asian (EAS)

AF:

0.000605

AC:

AN:

39688

South Asian (SAS)

AF:

0.0486

AC:

4193

AN:

86240

European-Finnish (FIN)

AF:

0.0263

AC:

1403

AN:

53410

Middle Eastern (MID)

AF:

0.0594

AC:

342

AN:

5756

European-Non Finnish (NFE)

AF:

0.0542

AC:

60262

AN:

1111350

Other (OTH)

AF:

0.0754

AC:

4550

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

4166

8332

12499

16665

20831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2432

4864

7296

9728

12160

<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:

0.155

AC:

23617

AN:

152174

Hom.:

3900

Cov.:

AF XY:

0.149

AC XY:

11114

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.419

AC:

17396

AN:

41470

American (AMR)

AF:

0.0914

AC:

1398

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0808

AC:

280

AN:

3466

East Asian (EAS)

AF:

0.00154

AC:

AN:

5184

South Asian (SAS)

AF:

0.0408

AC:

197

AN:

4826

European-Finnish (FIN)

AF:

0.0221

AC:

234

AN:

10608

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0554

AC:

3768

AN:

68012

Other (OTH)

AF:

0.125

AC:

265

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

796

1591

2387

3182

3978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

218

436

654

872

1090

<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:

0.0885

Hom.:

1623

Bravo

AF:

0.174

Asia WGS

AF:

0.0630

AC:

221

AN:

3476

EpiCase

AF:

0.0525

EpiControl

AF:

0.0508

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Donnai-Barrow syndrome (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

3.1

(source)

DANN

Benign

0.61

PhyloP100

-0.57

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over