NM_004525.3:c.12628A>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004525.3(LRP2):c.12628A>C(p.Ile4210Leu) variant causes a missense change. The variant allele was found at a frequency of 0.751 in 1,613,220 control chromosomes in the GnomAD database, including 468,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 33571 hom., cov: 31)

Exomes 𝑓: 0.76 ( 435398 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 6.26

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.6997403E-6).

BP6

Variant 2-169146922-T-G is Benign according to our data. Variant chr2-169146922-T-G is described in ClinVar as [Benign]. Clinvar id is 129501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169146922-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.12628A>C	p.Ile4210Leu	missense_variant	Exon 69 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.12499A>C	p.Ile4167Leu	missense_variant	Exon 68 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.11704A>C	p.Ile3902Leu	missense_variant	Exon 69 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.10339A>C	p.Ile3447Leu	missense_variant	Exon 54 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	ENST00000649046.1 link	c.12628A>C	p.Ile4210Leu	missense_variant	Exon 69 of 79	NM_004525.3	ENSP00000496870.1	P98164
LRP2	ENST00000649153.1 link	n.3526A>C		non_coding_transcript_exon_variant	Exon 21 of 30		ENSP00000497617.1	A0A3B3IT64
LRP2	ENST00000650252.1 link	n.*339A>C		non_coding_transcript_exon_variant	Exon 14 of 24		ENSP00000496887.1	A0A3B3IRR0
LRP2	ENST00000650252.1 link	n.*339A>C		3_prime_UTR_variant	Exon 14 of 24		ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes

AF:

0.618

AC:

93883

AN:

151832

Hom.:

33565

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.777

Gnomad AMR

AF:

0.737

Gnomad ASJ

AF:

0.843

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.795

Gnomad FIN

AF:

0.727

Gnomad MID

AF:

0.780

Gnomad NFE

AF:

0.790

Gnomad OTH

AF:

0.684

GnomAD3 exomes

AF:

0.724

AC:

181286

AN:

250362

Hom.:

68829

AF XY:

0.740

AC XY:

100131

AN XY:

135372

show subpopulations

Gnomad AFR exome

AF:

0.223

Gnomad AMR exome

AF:

0.781

Gnomad ASJ exome

AF:

0.843

Gnomad EAS exome

AF:

0.461

Gnomad SAS exome

AF:

0.806

Gnomad FIN exome

AF:

0.733

Gnomad NFE exome

AF:

0.785

Gnomad OTH exome

AF:

0.758

GnomAD4 exome

AF:

0.765

AC:

1117297

AN:

1461270

Hom.:

435398

Cov.:

AF XY:

0.768

AC XY:

558561

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.211

Gnomad4 AMR exome

AF:

0.776

Gnomad4 ASJ exome

AF:

0.845

Gnomad4 EAS exome

AF:

0.470

Gnomad4 SAS exome

AF:

0.804

Gnomad4 FIN exome

AF:

0.729

Gnomad4 NFE exome

AF:

0.790

Gnomad4 OTH exome

AF:

0.734

GnomAD4 genome

AF:

0.618

AC:

93903

AN:

151950

Hom.:

33571

Cov.:

AF XY:

0.620

AC XY:

46053

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.233

Gnomad4 AMR

AF:

0.737

Gnomad4 ASJ

AF:

0.843

Gnomad4 EAS

AF:

0.477

Gnomad4 SAS

AF:

0.795

Gnomad4 FIN

AF:

0.727

Gnomad4 NFE

AF:

0.790

Gnomad4 OTH

AF:

0.684

Alfa

AF:

0.759

Hom.:

115811

Bravo

AF:

0.596

TwinsUK

AF:

0.788

AC:

2922

ALSPAC

AF:

0.782

AC:

3012

ESP6500AA

AF:

0.242

AC:

1067

ESP6500EA

AF:

0.790

AC:

6795

ExAC

AF:

0.711

AC:

86367

Asia WGS

AF:

0.644

AC:

2239

AN:

3478

EpiCase

AF:

0.803

EpiControl

AF:

0.806

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

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

- -

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Donnai-Barrow syndrome

Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 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. -

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

This variant is associated with the following publications: (PMID: 17000706) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

.;T

MetaRNN

Benign

0.0000037

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

.;N

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0030

.;D

Polyphen

0.99

D;D

Vest4

0.16

MPC

1.7

ClinPred

0.055

GERP RS

4.5

Varity_R

0.73

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over