2-169259078-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.2460A>G(p.Thr820Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,612,380 control chromosomes in the GnomAD database, including 206,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23672 hom., cov: 30)

Exomes 𝑓: 0.49 ( 182740 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.419

Publications

31 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 2-169259078-T-C is Benign according to our data. Variant chr2-169259078-T-C is described in ClinVar as [Benign]. Clinvar id is 129510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.419 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.2460A>G	p.Thr820Thr	synonymous_variant	Exon 17 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.2460A>G	p.Thr820Thr	synonymous_variant	Exon 17 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.1536A>G	p.Thr512Thr	synonymous_variant	Exon 17 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.171A>G	p.Thr57Thr	synonymous_variant	Exon 2 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.2460A>G	p.Thr820Thr	synonymous_variant	Exon 17 of 79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.2049A>G	p.Thr683Thr	synonymous_variant	Exon 15 of 23	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.549

AC:

83113

AN:

151526

Hom.:

23636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.687

Gnomad AMI

AF:

0.440

Gnomad AMR

AF:

0.608

Gnomad ASJ

AF:

0.512

Gnomad EAS

AF:

0.478

Gnomad SAS

AF:

0.755

Gnomad FIN

AF:

0.387

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.470

Gnomad OTH

AF:

0.550

GnomAD2 exomes

AF:

0.546

AC:

137151

AN:

251078

AF XY:

0.548

show subpopulations

Gnomad AFR exome

AF:

0.694

Gnomad AMR exome

AF:

0.686

Gnomad ASJ exome

AF:

0.543

Gnomad EAS exome

AF:

0.476

Gnomad FIN exome

AF:

0.391

Gnomad NFE exome

AF:

0.470

Gnomad OTH exome

AF:

0.515

GnomAD4 exome

AF:

0.492

AC:

718665

AN:

1460736

Hom.:

182740

Cov.:

AF XY:

0.499

AC XY:

362906

AN XY:

726712

show subpopulations

African (AFR)

AF:

0.691

AC:

23105

AN:

33438

American (AMR)

AF:

0.677

AC:

30220

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.526

AC:

13724

AN:

26108

East Asian (EAS)

AF:

0.458

AC:

18170

AN:

39682

South Asian (SAS)

AF:

0.747

AC:

64389

AN:

86240

European-Finnish (FIN)

AF:

0.394

AC:

21038

AN:

53414

Middle Eastern (MID)

AF:

0.553

AC:

3184

AN:

5762

European-Non Finnish (NFE)

AF:

0.463

AC:

513971

AN:

1111122

Other (OTH)

AF:

0.512

AC:

30864

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

18934

37868

56803

75737

94671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15496

30992

46488

61984

77480

<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:

0.549

AC:

83203

AN:

151644

Hom.:

23672

Cov.:

AF XY:

0.550

AC XY:

40714

AN XY:

74086

show subpopulations

African (AFR)

AF:

0.687

AC:

28415

AN:

41348

American (AMR)

AF:

0.608

AC:

9257

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.512

AC:

1770

AN:

3458

East Asian (EAS)

AF:

0.478

AC:

2445

AN:

5116

South Asian (SAS)

AF:

0.752

AC:

3612

AN:

4800

European-Finnish (FIN)

AF:

0.387

AC:

4077

AN:

10530

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.470

AC:

31884

AN:

67864

Other (OTH)

AF:

0.555

AC:

1170

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1762

3524

5285

7047

8809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

716

1432

2148

2864

3580

<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:

0.502

Hom.:

38830

Bravo

AF:

0.567

Asia WGS

AF:

0.650

AC:

2260

AN:

3478

EpiCase

AF:

0.479

EpiControl

AF:

0.481

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

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

- -

Donnai-Barrow syndrome

Benign:2

Jan 12, 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

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.1

(source)

DANN

Benign

0.22

PhyloP100

0.42

Mutation Taster

=100/0

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