NM_004525.3:c.6035G>A

Variant names:

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.6035G>A(p.Arg2012Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,611,600 control chromosomes in the GnomAD database, including 650 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 (★★).

Frequency

Genomes: 𝑓 0.018 ( 66 hom., cov: 32)

Exomes 𝑓: 0.021 ( 584 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.66

Publications

15 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=0.0019096136).

BP6

Variant 2-169213662-C-T is Benign according to our data. Variant chr2-169213662-C-T is described in ClinVar as Benign. ClinVar VariationId is 259419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.6035G>A	p.Arg2012Lys	missense_variant	Exon 36 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.6035G>A	p.Arg2012Lys	missense_variant	Exon 36 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.5111G>A	p.Arg1704Lys	missense_variant	Exon 36 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.3746G>A	p.Arg1249Lys	missense_variant	Exon 21 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.6035G>A	p.Arg2012Lys	missense_variant	Exon 36 of 79		NM_004525.3	ENSP00000496870.1		P98164

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2785

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00420

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0577

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.0530

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0264

AC:

6577

AN:

248814

AF XY:

0.0235

show subpopulations

Gnomad AFR exome

AF:

0.00455

Gnomad AMR exome

AF:

0.0885

Gnomad ASJ exome

AF:

0.00696

Gnomad EAS exome

AF:

0.0461

Gnomad FIN exome

AF:

0.00836

Gnomad NFE exome

AF:

0.0169

Gnomad OTH exome

AF:

0.0219

GnomAD4 exome

AF:

0.0214

AC:

31238

AN:

1459340

Hom.:

584

Cov.:

AF XY:

0.0206

AC XY:

14988

AN XY:

726136

show subpopulations

African (AFR)

AF:

0.00363

AC:

121

AN:

33378

American (AMR)

AF:

0.0849

AC:

3793

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

188

AN:

26116

East Asian (EAS)

AF:

0.0785

AC:

3116

AN:

39684

South Asian (SAS)

AF:

0.0128

AC:

1102

AN:

86176

European-Finnish (FIN)

AF:

0.00876

AC:

468

AN:

53412

Middle Eastern (MID)

AF:

0.00988

AC:

AN:

4860

European-Non Finnish (NFE)

AF:

0.0190

AC:

21088

AN:

1110784

Other (OTH)

AF:

0.0218

AC:

1314

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1471

2942

4412

5883

7354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.0183

AC:

2792

AN:

152260

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1367

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00419

AC:

174

AN:

41556

American (AMR)

AF:

0.0579

AC:

886

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3466

East Asian (EAS)

AF:

0.0532

AC:

275

AN:

5172

South Asian (SAS)

AF:

0.0128

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00829

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0179

AC:

1216

AN:

68016

Other (OTH)

AF:

0.0180

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0192

Hom.:

132

Bravo

AF:

0.0208

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0236

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0203

AC:

175

ExAC

AF:

0.0234

AC:

2843

Asia WGS

AF:

0.0370

AC:

129

AN:

3478

EpiCase

AF:

0.0161

EpiControl

AF:

0.0154

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

Mar 03, 2015

GeneDx

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 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. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

0.098

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.057

T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.43

.;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.1

L;L

PhyloP100

2.7

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.13

.;N

REVEL

Benign

0.23

Sift

Benign

0.77

.;T

Sift4G

Uncertain

0.045

.;D

Polyphen

0.016

B;B

Vest4

0.023

MPC

0.25

ClinPred

0.012

GERP RS

2.2

Varity_R

0.042

gMVP

0.71

Mutation Taster

=91/9

polymorphism (auto)

(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