rs2229266

Positions:

chr2-169294161-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_004525.3(LRP2):c.639C>T(p.Asp213=) variant causes a synonymous change. The variant allele was found at a frequency of 0.28 in 1,602,868 control chromosomes in the GnomAD database, including 66,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7473 hom., cov: 31)

Exomes 𝑓: 0.28 ( 59287 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.09

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 2-169294161-G-A is Benign according to our data. Variant chr2-169294161-G-A is described in ClinVar as [Benign]. Clinvar id is 129533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169294161-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP2	NM_004525.3 linkuse as main transcript	c.639C>T	p.Asp213=	synonymous_variant	6/79	ENST00000649046.1
LRP2	XM_011511183.4 linkuse as main transcript	c.639C>T	p.Asp213=	synonymous_variant	6/78
LRP2	XM_047444340.1 linkuse as main transcript	c.-286C>T		5_prime_UTR_variant	6/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.639C>T	p.Asp213=	synonymous_variant	6/79		NM_004525.3	P1
LRP2	ENST00000443831.1 linkuse as main transcript	c.639C>T	p.Asp213=	synonymous_variant	6/23	2

Frequencies

GnomAD3 genomes

AF:

0.306

AC:

46427

AN:

151702

Hom.:

7465

Cov.:

show subpopulations

Gnomad AFR

AF:

0.334

Gnomad AMI

AF:

0.398

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.275

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.257

Gnomad OTH

AF:

0.296

GnomAD3 exomes

AF:

0.327

AC:

82118

AN:

251316

Hom.:

15358

AF XY:

0.315

AC XY:

42846

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.330

Gnomad AMR exome

AF:

0.546

Gnomad ASJ exome

AF:

0.258

Gnomad EAS exome

AF:

0.481

Gnomad SAS exome

AF:

0.324

Gnomad FIN exome

AF:

0.217

Gnomad NFE exome

AF:

0.264

Gnomad OTH exome

AF:

0.302

GnomAD4 exome

AF:

0.277

AC:

402433

AN:

1451048

Hom.:

59287

Cov.:

AF XY:

0.278

AC XY:

200550

AN XY:

722626

show subpopulations

Gnomad4 AFR exome

AF:

0.333

Gnomad4 AMR exome

AF:

0.537

Gnomad4 ASJ exome

AF:

0.267

Gnomad4 EAS exome

AF:

0.433

Gnomad4 SAS exome

AF:

0.328

Gnomad4 FIN exome

AF:

0.222

Gnomad4 NFE exome

AF:

0.258

Gnomad4 OTH exome

AF:

0.285

GnomAD4 genome

AF:

0.306

AC:

46474

AN:

151820

Hom.:

7473

Cov.:

AF XY:

0.307

AC XY:

22771

AN XY:

74170

show subpopulations

Gnomad4 AFR

AF:

0.334

Gnomad4 AMR

AF:

0.446

Gnomad4 ASJ

AF:

0.275

Gnomad4 EAS

AF:

0.458

Gnomad4 SAS

AF:

0.345

Gnomad4 FIN

AF:

0.222

Gnomad4 NFE

AF:

0.257

Gnomad4 OTH

AF:

0.297

Alfa

AF:

0.283

Hom.:

4580

Bravo

AF:

0.325

Asia WGS

AF:

0.410

AC:

1425

AN:

3478

EpiCase

AF:

0.253

EpiControl

AF:

0.260

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Donnai-Barrow syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over