chr2-169318824-T-C

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.248A>G(p.Asn83Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,613,762 control chromosomes in the GnomAD database, including 71,748 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 0.33 ( 8514 hom., cov: 32)

Exomes 𝑓: 0.29 ( 63234 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.752

Publications

35 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=9.2864037E-4).

BP6

Variant 2-169318824-T-C is Benign according to our data. Variant chr2-169318824-T-C is described in ClinVar as Benign. ClinVar VariationId is 129511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.248A>G	p.Asn83Ser	missense_variant	Exon 3 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.248A>G	p.Asn83Ser	missense_variant	Exon 3 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.-677A>G		5_prime_UTR_variant	Exon 3 of 79		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.248A>G	p.Asn83Ser	missense_variant	Exon 3 of 79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.248A>G	p.Asn83Ser	missense_variant	Exon 3 of 23	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49520

AN:

151936

Hom.:

8498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.448

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.237

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.276

Gnomad SAS

AF:

0.204

Gnomad FIN

AF:

0.263

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.320

GnomAD2 exomes

AF:

0.272

AC:

68407

AN:

251368

AF XY:

0.270

show subpopulations

Gnomad AFR exome

AF:

0.448

Gnomad AMR exome

AF:

0.163

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.280

Gnomad FIN exome

AF:

0.260

Gnomad NFE exome

AF:

0.295

Gnomad OTH exome

AF:

0.272

GnomAD4 exome

AF:

0.290

AC:

423737

AN:

1461708

Hom.:

63234

Cov.:

AF XY:

0.287

AC XY:

208996

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.452

AC:

15124

AN:

33474

American (AMR)

AF:

0.171

AC:

7625

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.334

AC:

8734

AN:

26134

East Asian (EAS)

AF:

0.289

AC:

11455

AN:

39696

South Asian (SAS)

AF:

0.198

AC:

17112

AN:

86256

European-Finnish (FIN)

AF:

0.260

AC:

13865

AN:

53416

Middle Eastern (MID)

AF:

0.278

AC:

1604

AN:

5766

European-Non Finnish (NFE)

AF:

0.297

AC:

330503

AN:

1111878

Other (OTH)

AF:

0.293

AC:

17715

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

17557

35114

52671

70228

87785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10888

21776

32664

43552

54440

<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:

0.326

AC:

49573

AN:

152054

Hom.:

8514

Cov.:

AF XY:

0.325

AC XY:

24126

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.448

AC:

18581

AN:

41462

American (AMR)

AF:

0.236

AC:

3605

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

1148

AN:

3470

East Asian (EAS)

AF:

0.276

AC:

1431

AN:

5176

South Asian (SAS)

AF:

0.204

AC:

984

AN:

4824

European-Finnish (FIN)

AF:

0.263

AC:

2781

AN:

10578

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.295

AC:

20073

AN:

67964

Other (OTH)

AF:

0.317

AC:

669

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1713

3426

5138

6851

8564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<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:

0.309

Hom.:

28534

Bravo

AF:

0.329

TwinsUK

AF:

0.286

AC:

1059

ALSPAC

AF:

0.294

AC:

1133

ESP6500AA

AF:

0.435

AC:

1915

ESP6500EA

AF:

0.293

AC:

2524

ExAC

AF:

0.278

AC:

33762

Asia WGS

AF:

0.228

AC:

796

AN:

3478

EpiCase

AF:

0.304

EpiControl

AF:

0.310

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: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

- -

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. -

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

0.064

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.072

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.15

T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.50

.;T;T

MetaRNN

Benign

0.00093

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.080

N;N;.

PhyloP100

-0.75

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.060

.;N;N

REVEL

Benign

0.13

Sift

Benign

0.82

.;T;T

Sift4G

Benign

0.74

.;T;T

Polyphen

0.0030

B;B;B

Vest4

0.083, 0.038

MPC

0.19

ClinPred

0.0000096

GERP RS

-6.3

Varity_R

0.042

gMVP

0.23

Mutation Taster

=93/7

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