rs830994

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.2025C>T(p.Val675Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,364 control chromosomes in the GnomAD database, including 341,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 29403 hom., cov: 33)

Exomes 𝑓: 0.65 ( 312379 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0940

Publications

33 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 2-169273018-G-A is Benign according to our data. Variant chr2-169273018-G-A is described in ClinVar as Benign. ClinVar VariationId is 129507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.094 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LRP2	NM_004525.3 link	c.2025C>T	p.Val675Val	synonymous_variant	Exon 15 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4 link	c.2025C>T	p.Val675Val	synonymous_variant	Exon 15 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.1101C>T	p.Val367Val	synonymous_variant	Exon 15 of 79		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LRP2	ENST00000649046.1 link	c.2025C>T	p.Val675Val	synonymous_variant	Exon 15 of 79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1 link	c.1818C>T	p.Val606Val	synonymous_variant	Exon 14 of 23	2		ENSP00000409813.1
LRP2	ENST00000493501.1 link	n.368C>T		non_coding_transcript_exon_variant	Exon 2 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.615

AC:

93399

AN:

151888

Hom.:

29400

Cov.:

show subpopulations

Gnomad AFR

AF:

0.519

Gnomad AMI

AF:

0.686

Gnomad AMR

AF:

0.541

Gnomad ASJ

AF:

0.701

Gnomad EAS

AF:

0.900

Gnomad SAS

AF:

0.515

Gnomad FIN

AF:

0.665

Gnomad MID

AF:

0.690

Gnomad NFE

AF:

0.661

Gnomad OTH

AF:

0.657

GnomAD2 exomes

AF:

0.628

AC:

157447

AN:

250798

AF XY:

0.628

show subpopulations

Gnomad AFR exome

AF:

0.517

Gnomad AMR exome

AF:

0.480

Gnomad ASJ exome

AF:

0.708

Gnomad EAS exome

AF:

0.917

Gnomad FIN exome

AF:

0.669

Gnomad NFE exome

AF:

0.659

Gnomad OTH exome

AF:

0.648

GnomAD4 exome

AF:

0.650

AC:

949919

AN:

1461358

Hom.:

312379

Cov.:

AF XY:

0.647

AC XY:

470252

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.526

AC:

17596

AN:

33442

American (AMR)

AF:

0.491

AC:

21898

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.706

AC:

18445

AN:

26118

East Asian (EAS)

AF:

0.858

AC:

34042

AN:

39696

South Asian (SAS)

AF:

0.506

AC:

43666

AN:

86250

European-Finnish (FIN)

AF:

0.672

AC:

35923

AN:

53420

Middle Eastern (MID)

AF:

0.721

AC:

4150

AN:

5758

European-Non Finnish (NFE)

AF:

0.661

AC:

734715

AN:

1111670

Other (OTH)

AF:

0.654

AC:

39484

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

19861

39722

59583

79444

99305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19102

38204

57306

76408

95510

<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:

0.615

AC:

93432

AN:

152006

Hom.:

29403

Cov.:

AF XY:

0.611

AC XY:

45415

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.519

AC:

21494

AN:

41452

American (AMR)

AF:

0.541

AC:

8257

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.701

AC:

2433

AN:

3472

East Asian (EAS)

AF:

0.900

AC:

4648

AN:

5166

South Asian (SAS)

AF:

0.514

AC:

2476

AN:

4814

European-Finnish (FIN)

AF:

0.665

AC:

7027

AN:

10572

Middle Eastern (MID)

AF:

0.680

AC:

200

AN:

294

European-Non Finnish (NFE)

AF:

0.661

AC:

44892

AN:

67952

Other (OTH)

AF:

0.655

AC:

1381

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1823

3646

5469

7292

9115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

768

1536

2304

3072

3840

<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:

0.639

Hom.:

41893

Bravo

AF:

0.611

Asia WGS

AF:

0.649

AC:

2256

AN:

3476

EpiCase

AF:

0.677

EpiControl

AF:

0.682

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Donnai-Barrow syndrome

Benign:2

Jan 12, 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. -

Aug 19, 2021

Genome-Nilou Lab

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

-0.33

CADD

Benign

5.8

(source)

DANN

Benign

0.72

PhyloP100

0.094

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