2-169173147-C-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.11092G>A(p.Val3698Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 1,614,150 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V3698V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0056 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 42 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.30

Publications

13 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=0.016275853).

BP6

Variant 2-169173147-C-T is Benign according to our data. Variant chr2-169173147-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00563 (857/152286) while in subpopulation AMR AF = 0.00876 (134/15294). AF 95% confidence interval is 0.00755. There are 7 homozygotes in GnomAd4. There are 419 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LRP2	NM_004525.3 link	c.11092G>A	p.Val3698Met	missense_variant	Exon 57 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_047444340.1 link	c.10168G>A	p.Val3390Met	missense_variant	Exon 57 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.8803G>A	p.Val2935Met	missense_variant	Exon 42 of 64		XP_011509486.1
LRP2	XM_011511183.4 link	c.11014+772G>A		intron_variant	Intron 56 of 77		XP_011509485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LRP2	ENST00000649046.1 link	c.11092G>A	p.Val3698Met	missense_variant	Exon 57 of 79	NM_004525.3	ENSP00000496870.1
LRP2	ENST00000649153.1 link	n.1990G>A		non_coding_transcript_exon_variant	Exon 9 of 30		ENSP00000497617.1
LRP2	ENST00000650252.1 link	n.124G>A		non_coding_transcript_exon_variant	Exon 2 of 24		ENSP00000496887.1

Frequencies

GnomAD3 genomes

AF:

0.00562

AC:

855

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00775

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00589

AC:

1482

AN:

251430

AF XY:

0.00586

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00601

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00804

Gnomad NFE exome

AF:

0.00723

Gnomad OTH exome

AF:

0.00929

GnomAD4 exome

AF:

0.00593

AC:

8676

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00604

AC XY:

4396

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

33480

American (AMR)

AF:

0.00715

AC:

320

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00543

AC:

142

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00453

AC:

391

AN:

86258

European-Finnish (FIN)

AF:

0.00790

AC:

422

AN:

53416

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00624

AC:

6938

AN:

1111994

Other (OTH)

AF:

0.00550

AC:

332

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

530

1060

1590

2120

2650

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

232

464

696

928

1160

<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:

0.00563

AC:

857

AN:

152286

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

419

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000987

AC:

AN:

41558

American (AMR)

AF:

0.00876

AC:

134

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.00331

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00782

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00775

AC:

527

AN:

68024

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00657

Hom.:

Bravo

AF:

0.00574

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00550

AC:

668

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00965

EpiControl

AF:

0.00699

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

May 24, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30900415, 26118977, 31216405) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LRP2: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 13, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Donnai-Barrow syndrome

Benign:4

Dec 31, 2017

Baylor Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jul 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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

- -

Nov 10, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

8.2

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.13

.;T

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

0.063

MutationAssessor

Benign

1.8

L;L

PhyloP100

1.3

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.76

.;N

REVEL

Uncertain

0.43

Sift

Benign

0.12

.;T

Sift4G

Uncertain

0.0040

.;D

Polyphen

0.61

P;P

Vest4

0.25

MVP

0.45

MPC

0.30

ClinPred

0.0081

GERP RS

-0.88

Varity_R

0.036

gMVP

0.49

Mutation Taster

=84/16

polymorphism

(source)

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

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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