rs2229268

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4BP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.11601T>C(p.Cys3867Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,812 control chromosomes in the GnomAD database, including 35,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2518 hom., cov: 30)

Exomes 𝑓: 0.21 ( 32723 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.07

Publications

20 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.232).

BP6

Variant 2-169168573-A-G is Benign according to our data. Variant chr2-169168573-A-G is described in ClinVar as Benign. ClinVar VariationId is 129493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.11601T>C	p.Cys3867Cys	synonymous_variant	Exon 61 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.11472T>C	p.Cys3824Cys	synonymous_variant	Exon 60 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.10677T>C	p.Cys3559Cys	synonymous_variant	Exon 61 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.9312T>C	p.Cys3104Cys	synonymous_variant	Exon 46 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	ENST00000649046.1 link	c.11601T>C	p.Cys3867Cys	synonymous_variant	Exon 61 of 79	NM_004525.3	ENSP00000496870.1	P98164
LRP2	ENST00000649153.1 link	n.2499T>C		non_coding_transcript_exon_variant	Exon 13 of 30		ENSP00000497617.1	A0A3B3IT64
LRP2	ENST00000650252.1 link	n.633T>C		non_coding_transcript_exon_variant	Exon 6 of 24		ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes

AF:

0.162

AC:

24561

AN:

152074

Hom.:

2521

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0396

Gnomad AMI

AF:

0.193

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.335

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.223

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.194

GnomAD2 exomes

AF:

0.203

AC:

51040

AN:

251298

AF XY:

0.214

show subpopulations

Gnomad AFR exome

AF:

0.0339

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.248

Gnomad EAS exome

AF:

0.344

Gnomad FIN exome

AF:

0.213

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.208

GnomAD4 exome

AF:

0.206

AC:

301656

AN:

1461620

Hom.:

32723

Cov.:

AF XY:

0.210

AC XY:

153036

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.0343

AC:

1148

AN:

33480

American (AMR)

AF:

0.106

AC:

4751

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.242

AC:

6321

AN:

26134

East Asian (EAS)

AF:

0.305

AC:

12100

AN:

39690

South Asian (SAS)

AF:

0.284

AC:

24511

AN:

86248

European-Finnish (FIN)

AF:

0.212

AC:

11307

AN:

53410

Middle Eastern (MID)

AF:

0.222

AC:

1283

AN:

5768

European-Non Finnish (NFE)

AF:

0.205

AC:

227705

AN:

1111782

Other (OTH)

AF:

0.208

AC:

12530

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

13498

26996

40494

53992

67490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7876

15752

23628

31504

39380

<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:

0.161

AC:

24555

AN:

152192

Hom.:

2518

Cov.:

AF XY:

0.162

AC XY:

12084

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0395

AC:

1639

AN:

41536

American (AMR)

AF:

0.126

AC:

1930

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

788

AN:

3472

East Asian (EAS)

AF:

0.337

AC:

1740

AN:

5164

South Asian (SAS)

AF:

0.289

AC:

1390

AN:

4812

European-Finnish (FIN)

AF:

0.209

AC:

2211

AN:

10604

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.209

AC:

14205

AN:

68000

Other (OTH)

AF:

0.195

AC:

412

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1014

2028

3041

4055

5069

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<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:

0.185

Hom.:

6832

Bravo

AF:

0.148

Asia WGS

AF:

0.273

AC:

948

AN:

3478

EpiCase

AF:

0.218

EpiControl

AF:

0.210

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Donnai-Barrow syndrome

Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.8

(source)

DANN

Benign

0.66

PhyloP100

2.1

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