2-169176479-C-T

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.10503G>A(p.Gln3501Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,744 control chromosomes in the GnomAD database, including 206,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 16472 hom., cov: 32)

Exomes 𝑓: 0.50 ( 189740 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.74

Publications

16 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 2-169176479-C-T is Benign according to our data. Variant chr2-169176479-C-T is described in CliVar as Benign. Clinvar id is 129490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169176479-C-T is described in CliVar as Benign. Clinvar id is 129490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.74 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.10503G>A	p.Gln3501Gln	synonymous_variant	Exon 54 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.10503G>A	p.Gln3501Gln	synonymous_variant	Exon 54 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.9579G>A	p.Gln3193Gln	synonymous_variant	Exon 54 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.8214G>A	p.Gln2738Gln	synonymous_variant	Exon 39 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.10503G>A	p.Gln3501Gln	synonymous_variant	Exon 54 of 79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000649153.1 link	n.1401G>A		non_coding_transcript_exon_variant	Exon 6 of 30			ENSP00000497617.1		A0A3B3IT64

Frequencies

GnomAD3 genomes

AF:

0.451

AC:

68471

AN:

151888

Hom.:

16459

Cov.:

show subpopulations

Gnomad AFR

AF:

0.320

Gnomad AMI

AF:

0.448

Gnomad AMR

AF:

0.602

Gnomad ASJ

AF:

0.452

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.479

Gnomad FIN

AF:

0.454

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.519

Gnomad OTH

AF:

0.467

GnomAD2 exomes

AF:

0.482

AC:

121013

AN:

251286

AF XY:

0.482

show subpopulations

Gnomad AFR exome

AF:

0.320

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.459

Gnomad EAS exome

AF:

0.0978

Gnomad FIN exome

AF:

0.455

Gnomad NFE exome

AF:

0.515

Gnomad OTH exome

AF:

0.499

GnomAD4 exome

AF:

0.503

AC:

734999

AN:

1461738

Hom.:

189740

Cov.:

AF XY:

0.502

AC XY:

365166

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.312

AC:

10446

AN:

33480

American (AMR)

AF:

0.658

AC:

29444

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.457

AC:

11932

AN:

26134

East Asian (EAS)

AF:

0.114

AC:

4508

AN:

39696

South Asian (SAS)

AF:

0.490

AC:

42291

AN:

86256

European-Finnish (FIN)

AF:

0.454

AC:

24242

AN:

53414

Middle Eastern (MID)

AF:

0.501

AC:

2890

AN:

5768

European-Non Finnish (NFE)

AF:

0.522

AC:

580537

AN:

1111884

Other (OTH)

AF:

0.475

AC:

28709

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20959

41917

62876

83834

104793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16520

33040

49560

66080

82600

<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:

0.451

AC:

68522

AN:

152006

Hom.:

16472

Cov.:

AF XY:

0.450

AC XY:

33439

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.320

AC:

13271

AN:

41432

American (AMR)

AF:

0.602

AC:

9212

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.452

AC:

1568

AN:

3470

East Asian (EAS)

AF:

0.104

AC:

535

AN:

5168

South Asian (SAS)

AF:

0.480

AC:

2312

AN:

4816

European-Finnish (FIN)

AF:

0.454

AC:

4791

AN:

10548

Middle Eastern (MID)

AF:

0.500

AC:

147

AN:

294

European-Non Finnish (NFE)

AF:

0.519

AC:

35293

AN:

67966

Other (OTH)

AF:

0.467

AC:

987

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1845

3690

5536

7381

9226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

628

1256

1884

2512

3140

<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:

0.481

Hom.:

35473

Bravo

AF:

0.454

Asia WGS

AF:

0.346

AC:

1203

AN:

3478

EpiCase

AF:

0.520

EpiControl

AF:

0.529

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 22, 2018

Eurofins Ntd Llc (ga)

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

- -

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

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.032

(source)

DANN

Benign

0.18

PhyloP100

-1.7

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