rs990626

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.13113C>T(p.Ile4371Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,610,642 control chromosomes in the GnomAD database, including 424,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 30943 hom., cov: 32)

Exomes 𝑓: 0.73 ( 393280 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.51

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=-0.34).

BP6

Variant 2-169140541-G-A is Benign according to our data. Variant chr2-169140541-G-A is described in ClinVar as Benign. ClinVar VariationId is 129502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.51 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.13113C>T	p.Ile4371Ile	synonymous_variant	Exon 72 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.12984C>T	p.Ile4328Ile	synonymous_variant	Exon 71 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.12189C>T	p.Ile4063Ile	synonymous_variant	Exon 72 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.10824C>T	p.Ile3608Ile	synonymous_variant	Exon 57 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	ENST00000649046.1 link	c.13113C>T	p.Ile4371Ile	synonymous_variant	Exon 72 of 79	NM_004525.3	ENSP00000496870.1	P98164
LRP2	ENST00000649153.1 link	n.4007-931C>T		intron_variant	Intron 23 of 29		ENSP00000497617.1	A0A3B3IT64
LRP2	ENST00000650252.1 link	n.*820-33C>T		intron_variant	Intron 16 of 23		ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes

AF:

0.609

AC:

92431

AN:

151894

Hom.:

30938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.316

Gnomad AMI

AF:

0.751

Gnomad AMR

AF:

0.681

Gnomad ASJ

AF:

0.633

Gnomad EAS

AF:

0.460

Gnomad SAS

AF:

0.779

Gnomad FIN

AF:

0.708

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.749

Gnomad OTH

AF:

0.631

GnomAD2 exomes

AF:

0.691

AC:

173322

AN:

250652

AF XY:

0.704

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.736

Gnomad ASJ exome

AF:

0.652

Gnomad EAS exome

AF:

0.465

Gnomad FIN exome

AF:

0.716

Gnomad NFE exome

AF:

0.746

Gnomad OTH exome

AF:

0.708

GnomAD4 exome

AF:

0.728

AC:

1062528

AN:

1458630

Hom.:

393280

Cov.:

AF XY:

0.731

AC XY:

530522

AN XY:

725800

show subpopulations

African (AFR)

AF:

0.298

AC:

9952

AN:

33406

American (AMR)

AF:

0.730

AC:

32636

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.653

AC:

17068

AN:

26120

East Asian (EAS)

AF:

0.428

AC:

16989

AN:

39672

South Asian (SAS)

AF:

0.773

AC:

66617

AN:

86168

European-Finnish (FIN)

AF:

0.715

AC:

38050

AN:

53254

Middle Eastern (MID)

AF:

0.724

AC:

4168

AN:

5758

European-Non Finnish (NFE)

AF:

0.753

AC:

835184

AN:

1109276

Other (OTH)

AF:

0.694

AC:

41864

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

13031

26063

39094

52126

65157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20054

40108

60162

80216

100270

<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:

0.608

AC:

92444

AN:

152012

Hom.:

30943

Cov.:

AF XY:

0.610

AC XY:

45323

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.316

AC:

13089

AN:

41448

American (AMR)

AF:

0.681

AC:

10407

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.633

AC:

2199

AN:

3472

East Asian (EAS)

AF:

0.462

AC:

2381

AN:

5158

South Asian (SAS)

AF:

0.779

AC:

3747

AN:

4812

European-Finnish (FIN)

AF:

0.708

AC:

7476

AN:

10566

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.749

AC:

50915

AN:

67968

Other (OTH)

AF:

0.631

AC:

1333

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1589

3178

4767

6356

7945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<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:

0.697

Hom.:

147671

Bravo

AF:

0.588

Asia WGS

AF:

0.613

AC:

2130

AN:

3478

EpiCase

AF:

0.750

EpiControl

AF:

0.749

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Donnai-Barrow syndrome

Benign:2

Aug 19, 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

-0.34

CADD

Benign

8.9

(source)

DANN

Benign

0.65

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -33

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