rs33954745

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.2376T>C(p.Asp792Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 1,613,034 control chromosomes in the GnomAD database, including 5,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.089 ( 681 hom., cov: 30)

Exomes 𝑓: 0.076 ( 4585 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.46

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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
Stickler syndrome
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P

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=-0.48).

BP6

Variant 2-169259162-A-G is Benign according to our data. Variant chr2-169259162-A-G is described in ClinVar as Benign. ClinVar VariationId is 129509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.46 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LRP2	NM_004525.3 link	c.2376T>C	p.Asp792Asp	synonymous_variant	Exon 17 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4 link	c.2376T>C	p.Asp792Asp	synonymous_variant	Exon 17 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.1452T>C	p.Asp484Asp	synonymous_variant	Exon 17 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.87T>C	p.Asp29Asp	synonymous_variant	Exon 2 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.2376T>C	p.Asp792Asp	synonymous_variant	Exon 17 of 79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1 link	c.1965T>C	p.Asp655Asp	synonymous_variant	Exon 15 of 23	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes

AF:

0.0892

AC:

13551

AN:

151912

Hom.:

678

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0896

Gnomad ASJ

AF:

0.114

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.0460

Gnomad FIN

AF:

0.0298

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0800

Gnomad OTH

AF:

0.0994

GnomAD2 exomes

AF:

0.0696

AC:

17457

AN:

250904

AF XY:

0.0696

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.0580

Gnomad ASJ exome

AF:

0.123

Gnomad EAS exome

AF:

0.00179

Gnomad FIN exome

AF:

0.0337

Gnomad NFE exome

AF:

0.0793

Gnomad OTH exome

AF:

0.0812

GnomAD4 exome

AF:

0.0756

AC:

110517

AN:

1461004

Hom.:

4585

Cov.:

AF XY:

0.0754

AC XY:

54827

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.136

AC:

4561

AN:

33444

American (AMR)

AF:

0.0611

AC:

2726

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

3018

AN:

26110

East Asian (EAS)

AF:

0.00169

AC:

AN:

39682

South Asian (SAS)

AF:

0.0557

AC:

4805

AN:

86238

European-Finnish (FIN)

AF:

0.0352

AC:

1878

AN:

53412

Middle Eastern (MID)

AF:

0.0972

AC:

560

AN:

5762

European-Non Finnish (NFE)

AF:

0.0793

AC:

88124

AN:

1111384

Other (OTH)

AF:

0.0792

AC:

4778

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

4916

9833

14749

19666

24582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3280

6560

9840

13120

16400

<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:

0.0893

AC:

13582

AN:

152030

Hom.:

681

Cov.:

AF XY:

0.0865

AC XY:

6429

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.134

AC:

5559

AN:

41490

American (AMR)

AF:

0.0895

AC:

1364

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

395

AN:

3462

East Asian (EAS)

AF:

0.00233

AC:

AN:

5150

South Asian (SAS)

AF:

0.0459

AC:

221

AN:

4820

European-Finnish (FIN)

AF:

0.0298

AC:

316

AN:

10614

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0800

AC:

5436

AN:

67936

Other (OTH)

AF:

0.0984

AC:

207

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

635

1269

1904

2538

3173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<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:

0.0949

Hom.:

606

Bravo

AF:

0.0957

Asia WGS

AF:

0.0510

AC:

179

AN:

3478

EpiCase

AF:

0.0831

EpiControl

AF:

0.0846

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Donnai-Barrow syndrome

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.1

(source)

DANN

Benign

0.57

PhyloP100

1.5

Mutation Taster

=99/1

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