rs142549310

Positions:

chr2-169173996-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_004525.3(LRP2):c.10937G>A(p.Arg3646His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,204 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 12 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 1.36

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 -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP2. . Trascript score misZ 4.5094 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Stickler syndrome, Donnai-Barrow syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.020164698).

BP6

Variant 2-169173996-C-T is Benign according to our data. Variant chr2-169173996-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 74222.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr2-169173996-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00276 (421/152350) while in subpopulation NFE AF= 0.00365 (248/68038). AF 95% confidence interval is 0.00327. There are 3 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3 linkuse as main transcript	c.10937G>A	p.Arg3646His	missense_variant	56/79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 linkuse as main transcript	c.10937G>A	p.Arg3646His	missense_variant	56/78		XP_011509485.1
LRP2	XM_047444340.1 linkuse as main transcript	c.10013G>A	p.Arg3338His	missense_variant	56/79		XP_047300296.1
LRP2	XM_011511184.3 linkuse as main transcript	c.8648G>A	p.Arg2883His	missense_variant	41/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.10937G>A	p.Arg3646His	missense_variant	56/79	NM_004525.3	ENSP00000496870.1	P98164
LRP2	ENST00000649153.1 linkuse as main transcript	n.1835G>A		non_coding_transcript_exon_variant	8/30		ENSP00000497617.1	A0A3B3IT64
LRP2	ENST00000650252.1 linkuse as main transcript	n.-32G>A		upstream_gene_variant			ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

421

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0138

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00364

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00238

AC:

599

AN:

251368

Hom.:

AF XY:

0.00234

AC XY:

318

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.00291

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00249

AC:

3634

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

1783

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000529

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0108

Gnomad4 NFE exome

AF:

0.00262

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.00276

AC:

421

AN:

152350

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

242

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0138

Gnomad4 NFE

AF:

0.00365

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00289

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00218

AC:

265

EpiCase

AF:

0.00245

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LRP2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Donnai-Barrow syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 05, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

LRP2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.45

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

.;D

MetaRNN

Benign

0.020

T;T

MetaSVM

Uncertain

0.033

MutationAssessor

Benign

0.89

L;L

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-3.0

.;D

REVEL

Uncertain

0.39

Sift

Benign

0.11

.;T

Sift4G

Benign

0.23

.;T

Polyphen

0.30

B;B

Vest4

0.26

MVP

0.58

MPC

0.31

ClinPred

0.037

GERP RS

0.87

Varity_R

0.047

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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