2-169176479-C-T

Position:

chr2-169176479-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.10503G>A(p.Gln3501=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,744 control chromosomes in the GnomAD database, including 206,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 16472 hom., cov: 32)

Exomes 𝑓: 0.50 ( 189740 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.74

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 2-169176479-C-T is Benign according to our data. Variant chr2-169176479-C-T is described in ClinVar as [Benign]. Clinvar id is 129490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169176479-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.74 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP2	NM_004525.3 linkuse as main transcript	c.10503G>A	p.Gln3501=	synonymous_variant	54/79	ENST00000649046.1
LRP2	XM_011511183.4 linkuse as main transcript	c.10503G>A	p.Gln3501=	synonymous_variant	54/78
LRP2	XM_047444340.1 linkuse as main transcript	c.9579G>A	p.Gln3193=	synonymous_variant	54/79
LRP2	XM_011511184.3 linkuse as main transcript	c.8214G>A	p.Gln2738=	synonymous_variant	39/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.10503G>A	p.Gln3501=	synonymous_variant	54/79		NM_004525.3	P1
LRP2	ENST00000649153.1 linkuse as main transcript	c.1404G>A	p.Gln468=	synonymous_variant, NMD_transcript_variant	6/30

Frequencies

GnomAD3 genomes

AF:

0.451

AC:

68471

AN:

151888

Hom.:

16459

Cov.:

show subpopulations

Gnomad AFR

AF:

0.320

Gnomad AMI

AF:

0.448

Gnomad AMR

AF:

0.602

Gnomad ASJ

AF:

0.452

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.479

Gnomad FIN

AF:

0.454

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.519

Gnomad OTH

AF:

0.467

GnomAD3 exomes

AF:

0.482

AC:

121013

AN:

251286

Hom.:

31570

AF XY:

0.482

AC XY:

65516

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.320

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.459

Gnomad EAS exome

AF:

0.0978

Gnomad SAS exome

AF:

0.489

Gnomad FIN exome

AF:

0.455

Gnomad NFE exome

AF:

0.515

Gnomad OTH exome

AF:

0.499

GnomAD4 exome

AF:

0.503

AC:

734999

AN:

1461738

Hom.:

189740

Cov.:

AF XY:

0.502

AC XY:

365166

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.312

Gnomad4 AMR exome

AF:

0.658

Gnomad4 ASJ exome

AF:

0.457

Gnomad4 EAS exome

AF:

0.114

Gnomad4 SAS exome

AF:

0.490

Gnomad4 FIN exome

AF:

0.454

Gnomad4 NFE exome

AF:

0.522

Gnomad4 OTH exome

AF:

0.475

GnomAD4 genome

AF:

0.451

AC:

68522

AN:

152006

Hom.:

16472

Cov.:

AF XY:

0.450

AC XY:

33439

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.320

Gnomad4 AMR

AF:

0.602

Gnomad4 ASJ

AF:

0.452

Gnomad4 EAS

AF:

0.104

Gnomad4 SAS

AF:

0.480

Gnomad4 FIN

AF:

0.454

Gnomad4 NFE

AF:

0.519

Gnomad4 OTH

AF:

0.467

Alfa

AF:

0.480

Hom.:

8143

Bravo

AF:

0.454

Asia WGS

AF:

0.346

AC:

1203

AN:

3478

EpiCase

AF:

0.520

EpiControl

AF:

0.529

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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+	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2018	- -

Donnai-Barrow syndrome

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.032

DANN

Benign

0.18

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