rs990626

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.13113C>T(p.Ile4371=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,610,642 control chromosomes in the GnomAD database, including 424,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 30943 hom., cov: 32)

Exomes 𝑓: 0.73 ( 393280 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.51

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 2-169140541-G-A is Benign according to our data. Variant chr2-169140541-G-A is described in ClinVar as [Benign]. Clinvar id is 129502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169140541-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.51 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP2	NM_004525.3 linkuse as main transcript	c.13113C>T	p.Ile4371=	synonymous_variant	72/79	ENST00000649046.1
LRP2	XM_011511183.4 linkuse as main transcript	c.12984C>T	p.Ile4328=	synonymous_variant	71/78
LRP2	XM_047444340.1 linkuse as main transcript	c.12189C>T	p.Ile4063=	synonymous_variant	72/79
LRP2	XM_011511184.3 linkuse as main transcript	c.10824C>T	p.Ile3608=	synonymous_variant	57/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
LRP2	ENST00000649046.1 linkuse as main transcript	c.13113C>T	p.Ile4371=	synonymous_variant	72/79	NM_004525.3	P1
LRP2	ENST00000649153.1 linkuse as main transcript	c.4009-931C>T		intron_variant, NMD_transcript_variant
LRP2	ENST00000650252.1 linkuse as main transcript	c.*820-33C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.609

AC:

92431

AN:

151894

Hom.:

30938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.316

Gnomad AMI

AF:

0.751

Gnomad AMR

AF:

0.681

Gnomad ASJ

AF:

0.633

Gnomad EAS

AF:

0.460

Gnomad SAS

AF:

0.779

Gnomad FIN

AF:

0.708

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.749

Gnomad OTH

AF:

0.631

GnomAD3 exomes

AF:

0.691

AC:

173322

AN:

250652

Hom.:

62007

AF XY:

0.704

AC XY:

95411

AN XY:

135440

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.736

Gnomad ASJ exome

AF:

0.652

Gnomad EAS exome

AF:

0.465

Gnomad SAS exome

AF:

0.773

Gnomad FIN exome

AF:

0.716

Gnomad NFE exome

AF:

0.746

Gnomad OTH exome

AF:

0.708

GnomAD4 exome

AF:

0.728

AC:

1062528

AN:

1458630

Hom.:

393280

Cov.:

AF XY:

0.731

AC XY:

530522

AN XY:

725800

show subpopulations

Gnomad4 AFR exome

AF:

0.298

Gnomad4 AMR exome

AF:

0.730

Gnomad4 ASJ exome

AF:

0.653

Gnomad4 EAS exome

AF:

0.428

Gnomad4 SAS exome

AF:

0.773

Gnomad4 FIN exome

AF:

0.715

Gnomad4 NFE exome

AF:

0.753

Gnomad4 OTH exome

AF:

0.694

GnomAD4 genome

AF:

0.608

AC:

92444

AN:

152012

Hom.:

30943

Cov.:

AF XY:

0.610

AC XY:

45323

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.316

Gnomad4 AMR

AF:

0.681

Gnomad4 ASJ

AF:

0.633

Gnomad4 EAS

AF:

0.462

Gnomad4 SAS

AF:

0.779

Gnomad4 FIN

AF:

0.708

Gnomad4 NFE

AF:

0.749

Gnomad4 OTH

AF:

0.631

Alfa

AF:

0.718

Hom.:

69689

Bravo

AF:

0.588

Asia WGS

AF:

0.613

AC:

2130

AN:

3478

EpiCase

AF:

0.750

EpiControl

AF:

0.749

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Donnai-Barrow syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.9

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -33

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