rs149469954

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004525.3(LRP2):c.5209C>T(p.Leu1737Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,992 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.786

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062796474).

BP6

Variant 2-169231732-G-A is Benign according to our data. Variant chr2-169231732-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211399.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00125 (191/152242) while in subpopulation NFE AF = 0.00171 (116/68024). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.5209C>T	p.Leu1737Phe	missense_variant	Exon 31 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.5209C>T	p.Leu1737Phe	missense_variant	Exon 31 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.4285C>T	p.Leu1429Phe	missense_variant	Exon 31 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.2920C>T	p.Leu974Phe	missense_variant	Exon 16 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.5209C>T	p.Leu1737Phe	missense_variant	Exon 31 of 79		NM_004525.3	ENSP00000496870.1		P98164

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

191

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00120

AC:

300

AN:

250994

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00154

AC:

2256

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1083

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33468

American (AMR)

AF:

0.000738

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00907

AC:

237

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000655

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00162

AC:

1800

AN:

1111934

Other (OTH)

AF:

0.00232

AC:

140

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

127

254

380

507

634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00125

AC:

191

AN:

152242

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41548

American (AMR)

AF:

0.00124

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00171

AC:

116

AN:

68024

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00155

Hom.:

Bravo

AF:

0.00122

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00105

AC:

127

EpiCase

AF:

0.00147

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25533962) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LRP2: BS2 -

Donnai-Barrow syndrome

Benign:2

May 22, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Sep 12, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LRP2-related disorder

Benign:1

Dec 12, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.35

CADD

Benign

5.9

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.080

T;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.76

.;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.0063

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.7

L;L

PhyloP100

0.79

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.010

.;N

REVEL

Benign

0.20

Sift

Benign

0.052

.;T

Sift4G

Uncertain

0.021

.;D

Polyphen

0.40

B;B

Vest4

0.036

MVP

0.19

MPC

0.30

ClinPred

0.016

GERP RS

-0.28

Varity_R

0.049

gMVP

0.26

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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