2-169146922-T-G

Position:

chr2-169146922-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_004525.3(LRP2):c.12628A>C(p.Ile4210Leu) variant causes a missense change. The variant allele was found at a frequency of 0.751 in 1,613,220 control chromosomes in the GnomAD database, including 468,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I4210I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.62 ( 33571 hom., cov: 31)

Exomes 𝑓: 0.76 ( 435398 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.26

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=3.6997403E-6).

BP6

Variant 2-169146922-T-G is Benign according to our data. Variant chr2-169146922-T-G is described in ClinVar as [Benign]. Clinvar id is 129501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169146922-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP2	NM_004525.3 linkuse as main transcript	c.12628A>C	p.Ile4210Leu	missense_variant	69/79	ENST00000649046.1
LRP2	XM_011511183.4 linkuse as main transcript	c.12499A>C	p.Ile4167Leu	missense_variant	68/78
LRP2	XM_047444340.1 linkuse as main transcript	c.11704A>C	p.Ile3902Leu	missense_variant	69/79
LRP2	XM_011511184.3 linkuse as main transcript	c.10339A>C	p.Ile3447Leu	missense_variant	54/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
LRP2	ENST00000649046.1 linkuse as main transcript	c.12628A>C	p.Ile4210Leu	missense_variant	69/79	NM_004525.3	P1
LRP2	ENST00000649153.1 linkuse as main transcript	c.3529A>C	p.Ile1177Leu	missense_variant, NMD_transcript_variant	21/30
LRP2	ENST00000650252.1 linkuse as main transcript	c.*339A>C		3_prime_UTR_variant, NMD_transcript_variant	14/24

Frequencies

GnomAD3 genomes

AF:

0.618

AC:

93883

AN:

151832

Hom.:

33565

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.777

Gnomad AMR

AF:

0.737

Gnomad ASJ

AF:

0.843

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.795

Gnomad FIN

AF:

0.727

Gnomad MID

AF:

0.780

Gnomad NFE

AF:

0.790

Gnomad OTH

AF:

0.684

GnomAD3 exomes

AF:

0.724

AC:

181286

AN:

250362

Hom.:

68829

AF XY:

0.740

AC XY:

100131

AN XY:

135372

show subpopulations

Gnomad AFR exome

AF:

0.223

Gnomad AMR exome

AF:

0.781

Gnomad ASJ exome

AF:

0.843

Gnomad EAS exome

AF:

0.461

Gnomad SAS exome

AF:

0.806

Gnomad FIN exome

AF:

0.733

Gnomad NFE exome

AF:

0.785

Gnomad OTH exome

AF:

0.758

GnomAD4 exome

AF:

0.765

AC:

1117297

AN:

1461270

Hom.:

435398

Cov.:

AF XY:

0.768

AC XY:

558561

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.211

Gnomad4 AMR exome

AF:

0.776

Gnomad4 ASJ exome

AF:

0.845

Gnomad4 EAS exome

AF:

0.470

Gnomad4 SAS exome

AF:

0.804

Gnomad4 FIN exome

AF:

0.729

Gnomad4 NFE exome

AF:

0.790

Gnomad4 OTH exome

AF:

0.734

GnomAD4 genome

AF:

0.618

AC:

93903

AN:

151950

Hom.:

33571

Cov.:

AF XY:

0.620

AC XY:

46053

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.233

Gnomad4 AMR

AF:

0.737

Gnomad4 ASJ

AF:

0.843

Gnomad4 EAS

AF:

0.477

Gnomad4 SAS

AF:

0.795

Gnomad4 FIN

AF:

0.727

Gnomad4 NFE

AF:

0.790

Gnomad4 OTH

AF:

0.684

Alfa

AF:

0.759

Hom.:

115811

Bravo

AF:

0.596

TwinsUK

AF:

0.788

AC:

2922

ALSPAC

AF:

0.782

AC:

3012

ESP6500AA

AF:

0.242

AC:

1067

ESP6500EA

AF:

0.790

AC:

6795

ExAC

AF:

0.711

AC:

86367

Asia WGS

AF:

0.644

AC:

2239

AN:

3478

EpiCase

AF:

0.803

EpiControl

AF:

0.806

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	-	- -

Donnai-Barrow syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17000706) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

.;T

MetaRNN

Benign

0.0000037

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

5.2e-8

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

.;N

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0030

.;D

Polyphen

0.99

D;D

Vest4

0.16

MPC

1.7

ClinPred

0.055

GERP RS

4.5

Varity_R

0.73

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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