2-169154475-T-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.12280A>G(p.Lys4094Glu) variant causes a missense change. The variant allele was found at a frequency of 0.762 in 1,610,506 control chromosomes in the GnomAD database, including 470,910 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.79 ( 48286 hom., cov: 31)

Exomes 𝑓: 0.76 ( 422624 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.87

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=9.058307E-7).

BP6

Variant 2-169154475-T-C is Benign according to our data. Variant chr2-169154475-T-C is described in ClinVar as [Benign]. Clinvar id is 129500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169154475-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.12280A>G	p.Lys4094Glu	missense_variant	Exon 66 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.12151A>G	p.Lys4051Glu	missense_variant	Exon 65 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.11356A>G	p.Lys3786Glu	missense_variant	Exon 66 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.9991A>G	p.Lys3331Glu	missense_variant	Exon 51 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	ENST00000649046.1 link	c.12280A>G	p.Lys4094Glu	missense_variant	Exon 66 of 79	NM_004525.3	ENSP00000496870.1	P98164
LRP2	ENST00000649153.1 link	n.3178A>G		non_coding_transcript_exon_variant	Exon 18 of 30		ENSP00000497617.1	A0A3B3IT64
LRP2	ENST00000650252.1 link	n.1308A>G		non_coding_transcript_exon_variant	Exon 11 of 24		ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes

AF:

0.792

AC:

120398

AN:

151984

Hom.:

48230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.894

Gnomad AMI

AF:

0.725

Gnomad AMR

AF:

0.805

Gnomad ASJ

AF:

0.739

Gnomad EAS

AF:

0.495

Gnomad SAS

AF:

0.858

Gnomad FIN

AF:

0.715

Gnomad MID

AF:

0.858

Gnomad NFE

AF:

0.761

Gnomad OTH

AF:

0.791

GnomAD3 exomes

AF:

0.761

AC:

191130

AN:

251178

Hom.:

73839

AF XY:

0.765

AC XY:

103846

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.898

Gnomad AMR exome

AF:

0.800

Gnomad ASJ exome

AF:

0.763

Gnomad EAS exome

AF:

0.493

Gnomad SAS exome

AF:

0.860

Gnomad FIN exome

AF:

0.720

Gnomad NFE exome

AF:

0.754

Gnomad OTH exome

AF:

0.762

GnomAD4 exome

AF:

0.758

AC:

1106038

AN:

1458404

Hom.:

422624

Cov.:

AF XY:

0.761

AC XY:

552486

AN XY:

725716

show subpopulations

Gnomad4 AFR exome

AF:

0.900

Gnomad4 AMR exome

AF:

0.802

Gnomad4 ASJ exome

AF:

0.756

Gnomad4 EAS exome

AF:

0.470

Gnomad4 SAS exome

AF:

0.855

Gnomad4 FIN exome

AF:

0.717

Gnomad4 NFE exome

AF:

0.757

Gnomad4 OTH exome

AF:

0.758

GnomAD4 genome

AF:

0.792

AC:

120517

AN:

152102

Hom.:

48286

Cov.:

AF XY:

0.790

AC XY:

58735

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.894

Gnomad4 AMR

AF:

0.805

Gnomad4 ASJ

AF:

0.739

Gnomad4 EAS

AF:

0.496

Gnomad4 SAS

AF:

0.856

Gnomad4 FIN

AF:

0.715

Gnomad4 NFE

AF:

0.761

Gnomad4 OTH

AF:

0.792

Alfa

AF:

0.761

Hom.:

98387

Bravo

AF:

0.799

TwinsUK

AF:

0.763

AC:

2829

ALSPAC

AF:

0.734

AC:

2827

ESP6500AA

AF:

0.885

AC:

3900

ESP6500EA

AF:

0.758

AC:

6522

ExAC

AF:

0.762

AC:

92507

Asia WGS

AF:

0.726

AC:

2526

AN:

3478

EpiCase

AF:

0.769

EpiControl

AF:

0.771

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

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

- -

not provided

Benign:3

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: 30476138) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.34

DEOGEN2

Benign

0.048

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.34

.;T

MetaRNN

Benign

9.1e-7

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.3

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.93

.;N

REVEL

Uncertain

0.35

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

.;T

Polyphen

0.0

B;B

Vest4

0.024

MPC

0.94

ClinPred

0.0093

GERP RS

5.5

Varity_R

0.14

gMVP

0.71

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

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