2-169173147-C-T

Position:

chr2-169173147-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004525.3(LRP2):c.11092G>A(p.Val3698Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 1,614,150 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 42 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.30

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.

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=0.016275853).

BP6

Variant 2-169173147-C-T is Benign according to our data. Variant chr2-169173147-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169173147-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00563 (857/152286) while in subpopulation AMR AF= 0.00876 (134/15294). AF 95% confidence interval is 0.00755. There are 7 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LRP2	NM_004525.3 linkuse as main transcript	c.11092G>A	p.Val3698Met	missense_variant	57/79	ENST00000649046.1	NP_004516.2
LRP2	XM_047444340.1 linkuse as main transcript	c.10168G>A	p.Val3390Met	missense_variant	57/79		XP_047300296.1
LRP2	XM_011511184.3 linkuse as main transcript	c.8803G>A	p.Val2935Met	missense_variant	42/64		XP_011509486.1
LRP2	XM_011511183.4 linkuse as main transcript	c.11014+772G>A		intron_variant			XP_011509485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
LRP2	ENST00000649046.1 linkuse as main transcript	c.11092G>A	p.Val3698Met	missense_variant	57/79	NM_004525.3	ENSP00000496870	P1
LRP2	ENST00000649153.1 linkuse as main transcript	c.1993G>A	p.Val665Met	missense_variant, NMD_transcript_variant	9/30		ENSP00000497617
LRP2	ENST00000650252.1 linkuse as main transcript	c.124G>A	p.Val42Met	missense_variant, NMD_transcript_variant	2/24		ENSP00000496887

Frequencies

GnomAD3 genomes

AF:

0.00562

AC:

855

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00775

Gnomad OTH

AF:

0.00957

GnomAD3 exomes

AF:

0.00589

AC:

1482

AN:

251430

Hom.:

AF XY:

0.00586

AC XY:

796

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00601

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00490

Gnomad FIN exome

AF:

0.00804

Gnomad NFE exome

AF:

0.00723

Gnomad OTH exome

AF:

0.00929

GnomAD4 exome

AF:

0.00593

AC:

8676

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00604

AC XY:

4396

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.00715

Gnomad4 ASJ exome

AF:

0.00543

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00453

Gnomad4 FIN exome

AF:

0.00790

Gnomad4 NFE exome

AF:

0.00624

Gnomad4 OTH exome

AF:

0.00550

GnomAD4 genome

AF:

0.00563

AC:

857

AN:

152286

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

419

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000987

Gnomad4 AMR

AF:

0.00876

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.00782

Gnomad4 NFE

AF:

0.00775

Gnomad4 OTH

AF:

0.00947

Alfa

AF:

0.00681

Hom.:

Bravo

AF:

0.00574

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00550

AC:

668

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00965

EpiControl

AF:

0.00699

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 13, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	This variant is associated with the following publications: (PMID: 30900415, 26118977, 31216405) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LRP2: BS2 -

Donnai-Barrow syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 10, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

8.2

DANN

Benign

0.90

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.13

.;T

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

0.063

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.76

.;N

REVEL

Uncertain

0.43

Sift

Benign

0.12

.;T

Sift4G

Uncertain

0.0040

.;D

Polyphen

0.61

P;P

Vest4

0.25

MVP

0.45

MPC

0.30

ClinPred

0.0081

GERP RS

-0.88

Varity_R

0.036

gMVP

0.49

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