rs830973

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004525.3(LRP2):c.4294+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,613,190 control chromosomes in the GnomAD database, including 98,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10353 hom., cov: 32)

Exomes 𝑓: 0.34 ( 88019 hom. )

Consequence

LRP2
NM_004525.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.24

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-169239508-G-A is Benign according to our data. Variant chr2-169239508-G-A is described in ClinVar as [Benign]. Clinvar id is 259418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169239508-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
LRP2	NM_004525.3 linkuse as main transcript	c.4294+19C>T	intron_variant	ENST00000649046.1
LRP2	XM_011511183.4 linkuse as main transcript	c.4294+19C>T	intron_variant
LRP2	XM_011511184.3 linkuse as main transcript	c.2005+19C>T	intron_variant
LRP2	XM_047444340.1 linkuse as main transcript	c.3370+19C>T	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.4294+19C>T		intron_variant			NM_004525.3	P1

Frequencies

GnomAD3 genomes

AF:

0.363

AC:

55059

AN:

151804

Hom.:

10336

Cov.:

show subpopulations

Gnomad AFR

AF:

0.390

Gnomad AMI

AF:

0.259

Gnomad AMR

AF:

0.455

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.467

Gnomad SAS

AF:

0.587

Gnomad FIN

AF:

0.304

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.313

Gnomad OTH

AF:

0.356

GnomAD3 exomes

AF:

0.400

AC:

100412

AN:

251200

Hom.:

22035

AF XY:

0.400

AC XY:

54344

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.583

Gnomad ASJ exome

AF:

0.353

Gnomad EAS exome

AF:

0.466

Gnomad SAS exome

AF:

0.571

Gnomad FIN exome

AF:

0.303

Gnomad NFE exome

AF:

0.313

Gnomad OTH exome

AF:

0.350

GnomAD4 exome

AF:

0.336

AC:

491461

AN:

1461268

Hom.:

88019

Cov.:

AF XY:

0.342

AC XY:

248876

AN XY:

726950

show subpopulations

Gnomad4 AFR exome

AF:

0.390

Gnomad4 AMR exome

AF:

0.568

Gnomad4 ASJ exome

AF:

0.348

Gnomad4 EAS exome

AF:

0.445

Gnomad4 SAS exome

AF:

0.567

Gnomad4 FIN exome

AF:

0.304

Gnomad4 NFE exome

AF:

0.304

Gnomad4 OTH exome

AF:

0.350

GnomAD4 genome

AF:

0.363

AC:

55102

AN:

151922

Hom.:

10353

Cov.:

AF XY:

0.368

AC XY:

27334

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.390

Gnomad4 AMR

AF:

0.455

Gnomad4 ASJ

AF:

0.342

Gnomad4 EAS

AF:

0.468

Gnomad4 SAS

AF:

0.585

Gnomad4 FIN

AF:

0.304

Gnomad4 NFE

AF:

0.313

Gnomad4 OTH

AF:

0.363

Alfa

AF:

0.341

Hom.:

4958

Bravo

AF:

0.373

Asia WGS

AF:

0.527

AC:

1831

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Donnai-Barrow syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

Cadd

Benign

8.3

Dann

Benign

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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