NM_004525.3:c.3452C>T

Variant names:

Variant summary

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

The NM_004525.3(LRP2):c.3452C>T(p.Pro1151Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00662 in 1,614,060 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 22 hom., cov: 32)

Exomes 𝑓: 0.0060 ( 104 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.07

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004464656).

BP6

Variant 2-169243501-G-A is Benign according to our data. Variant chr2-169243501-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1968/152262) while in subpopulation AFR AF = 0.0306 (1272/41530). AF 95% confidence interval is 0.0292. There are 22 homozygotes in GnomAd4. There are 960 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.3452C>T	p.Pro1151Leu	missense_variant	Exon 23 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.3452C>T	p.Pro1151Leu	missense_variant	Exon 23 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.2528C>T	p.Pro843Leu	missense_variant	Exon 23 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.1163C>T	p.Pro388Leu	missense_variant	Exon 8 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.3452C>T	p.Pro1151Leu	missense_variant	Exon 23 of 79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.3041C>T	p.Pro1014Leu	missense_variant	Exon 21 of 23	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1963

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0305

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.00943

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.00413

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.00923

AC:

2322

AN:

251464

AF XY:

0.00934

show subpopulations

Gnomad AFR exome

AF:

0.0303

Gnomad AMR exome

AF:

0.00529

Gnomad ASJ exome

AF:

0.0361

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00539

Gnomad OTH exome

AF:

0.0109

GnomAD4 exome

AF:

0.00596

AC:

8718

AN:

1461798

Hom.:

104

Cov.:

AF XY:

0.00649

AC XY:

4720

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0339

AC:

1135

AN:

33472

American (AMR)

AF:

0.00570

AC:

255

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0344

AC:

898

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39696

South Asian (SAS)

AF:

0.0187

AC:

1616

AN:

86254

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0345

AC:

199

AN:

5768

European-Non Finnish (NFE)

AF:

0.00356

AC:

3964

AN:

1111948

Other (OTH)

AF:

0.0105

AC:

637

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

472

944

1416

1888

2360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.0129

AC:

1968

AN:

152262

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

960

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0306

AC:

1272

AN:

41530

American (AMR)

AF:

0.00941

AC:

144

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.0160

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00412

AC:

280

AN:

68028

Other (OTH)

AF:

0.0185

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

197

296

394

493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00831

Hom.:

Bravo

AF:

0.0137

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.0275

AC:

121

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00992

AC:

1204

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.00862

EpiControl

AF:

0.00907

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

Aug 05, 2025

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

not specified

Benign:3

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

- -

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:3

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. -

Aug 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;D;D

Eigen

Benign

-0.071

Eigen_PC

Benign

-0.066

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

.;D;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Uncertain

0.029

MutationAssessor

Benign

1.7

L;L;.

PhyloP100

7.1

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.4

.;D;D

REVEL

Uncertain

0.49

Sift

Benign

0.58

.;T;T

Sift4G

Uncertain

0.0050

.;D;T

Polyphen

0.41

B;B;B

Vest4

0.45, 0.52

MVP

0.64

MPC

0.39

ClinPred

0.050

GERP RS

5.0

Varity_R

0.073

gMVP

0.72

Mutation Taster

=59/41

polymorphism

(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

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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