rs34693334

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004525.3(LRP2):c.775G>C(p.Gly259Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0651 in 1,613,654 control chromosomes in the GnomAD database, including 4,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G259S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.056 ( 353 hom., cov: 31)

Exomes 𝑓: 0.066 ( 3800 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.687

Publications

19 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=0.0017864704).

BP6

Variant 2-169290992-C-G is Benign according to our data. Variant chr2-169290992-C-G is described in ClinVar as [Benign]. Clinvar id is 129539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.775G>C	p.Gly259Arg	missense_variant	Exon 8 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.775G>C	p.Gly259Arg	missense_variant	Exon 8 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.-150G>C		5_prime_UTR_variant	Exon 8 of 79		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.775G>C	p.Gly259Arg	missense_variant	Exon 8 of 79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.775G>C	p.Gly259Arg	missense_variant	Exon 8 of 23	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.0557

AC:

8475

AN:

152048

Hom.:

354

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0203

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.0492

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0772

Gnomad FIN

AF:

0.0874

Gnomad MID

AF:

0.143

Gnomad NFE

AF:

0.0697

Gnomad OTH

AF:

0.0621

GnomAD2 exomes

AF:

0.0637

AC:

15985

AN:

250840

AF XY:

0.0665

show subpopulations

Gnomad AFR exome

AF:

0.0210

Gnomad AMR exome

AF:

0.0345

Gnomad ASJ exome

AF:

0.179

Gnomad EAS exome

AF:

0.000979

Gnomad FIN exome

AF:

0.0832

Gnomad NFE exome

AF:

0.0691

Gnomad OTH exome

AF:

0.0827

GnomAD4 exome

AF:

0.0661

AC:

96590

AN:

1461488

Hom.:

3800

Cov.:

AF XY:

0.0677

AC XY:

49187

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.0202

AC:

675

AN:

33468

American (AMR)

AF:

0.0367

AC:

1641

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4715

AN:

26130

East Asian (EAS)

AF:

0.000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.0854

AC:

7365

AN:

86218

European-Finnish (FIN)

AF:

0.0837

AC:

4469

AN:

53412

Middle Eastern (MID)

AF:

0.123

AC:

711

AN:

5764

European-Non Finnish (NFE)

AF:

0.0654

AC:

72724

AN:

1111704

Other (OTH)

AF:

0.0707

AC:

4270

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

4266

8531

12797

17062

21328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0557

AC:

8475

AN:

152166

Hom.:

353

Cov.:

AF XY:

0.0567

AC XY:

4214

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0203

AC:

843

AN:

41536

American (AMR)

AF:

0.0492

AC:

752

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

629

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5180

South Asian (SAS)

AF:

0.0773

AC:

371

AN:

4802

European-Finnish (FIN)

AF:

0.0874

AC:

924

AN:

10570

Middle Eastern (MID)

AF:

0.147

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0697

AC:

4739

AN:

68000

Other (OTH)

AF:

0.0610

AC:

129

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

393

786

1180

1573

1966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0698

Hom.:

388

Bravo

AF:

0.0510

TwinsUK

AF:

0.0677

AC:

251

ALSPAC

AF:

0.0636

AC:

245

ESP6500AA

AF:

0.0254

AC:

112

ESP6500EA

AF:

0.0707

AC:

608

ExAC

AF:

0.0630

AC:

7655

Asia WGS

AF:

0.0340

AC:

119

AN:

3478

EpiCase

AF:

0.0728

EpiControl

AF:

0.0741

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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:2

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.4

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.068

T;T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.20

.;T;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-0.34

N;N;.

PhyloP100

0.69

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.20

.;N;N

REVEL

Benign

0.077

Sift

Benign

0.54

.;T;T

Sift4G

Uncertain

0.060

.;T;T

Polyphen

0.013

B;B;B

Vest4

0.080, 0.039

MPC

0.28

ClinPred

0.0018

GERP RS

2.7

Varity_R

0.030

gMVP

0.47

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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rs34693334

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