2-169205568-G-C

Position:

chr2-169205568-G-C

Variant summary

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

The NM_004525.3(LRP2):c.7626C>G(p.Arg2542=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0677 in 1,613,650 control chromosomes in the GnomAD database, including 6,434 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. R2542R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 2161 hom., cov: 32)

Exomes 𝑓: 0.062 ( 4273 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.288

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=-0.73).

BP6

Variant 2-169205568-G-C is Benign according to our data. Variant chr2-169205568-G-C is described in ClinVar as [Benign]. Clinvar id is 129536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169205568-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.288 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP2	NM_004525.3 linkuse as main transcript	c.7626C>G	p.Arg2542=	synonymous_variant	41/79	ENST00000649046.1
LRP2	XM_011511183.4 linkuse as main transcript	c.7626C>G	p.Arg2542=	synonymous_variant	41/78
LRP2	XM_047444340.1 linkuse as main transcript	c.6702C>G	p.Arg2234=	synonymous_variant	41/79
LRP2	XM_011511184.3 linkuse as main transcript	c.5337C>G	p.Arg1779=	synonymous_variant	26/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.7626C>G	p.Arg2542=	synonymous_variant	41/79		NM_004525.3	P1

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18804

AN:

151834

Hom.:

2156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.307

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0691

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.0494

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0538

Gnomad OTH

AF:

0.0954

GnomAD3 exomes

AF:

0.0688

AC:

17308

AN:

251426

Hom.:

1217

AF XY:

0.0666

AC XY:

9054

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.313

Gnomad AMR exome

AF:

0.0351

Gnomad ASJ exome

AF:

0.0271

Gnomad EAS exome

AF:

0.00392

Gnomad SAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.0475

Gnomad NFE exome

AF:

0.0541

Gnomad OTH exome

AF:

0.0618

GnomAD4 exome

AF:

0.0619

AC:

90493

AN:

1461698

Hom.:

4273

Cov.:

AF XY:

0.0623

AC XY:

45281

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.319

Gnomad4 AMR exome

AF:

0.0396

Gnomad4 ASJ exome

AF:

0.0237

Gnomad4 EAS exome

AF:

0.00207

Gnomad4 SAS exome

AF:

0.0986

Gnomad4 FIN exome

AF:

0.0460

Gnomad4 NFE exome

AF:

0.0557

Gnomad4 OTH exome

AF:

0.0695

GnomAD4 genome

AF:

0.124

AC:

18830

AN:

151952

Hom.:

2161

Cov.:

AF XY:

0.122

AC XY:

9061

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.307

Gnomad4 AMR

AF:

0.0689

Gnomad4 ASJ

AF:

0.0248

Gnomad4 EAS

AF:

0.00425

Gnomad4 SAS

AF:

0.0997

Gnomad4 FIN

AF:

0.0494

Gnomad4 NFE

AF:

0.0538

Gnomad4 OTH

AF:

0.0944

Alfa

AF:

0.0424

Hom.:

Bravo

AF:

0.133

Asia WGS

AF:

0.0710

AC:

247

AN:

3478

EpiCase

AF:

0.0539

EpiControl

AF:

0.0538

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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	-	- -

Donnai-Barrow syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	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

-0.73

CADD

Benign

5.6

DANN

Benign

0.67

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