rs34915742

Positions:

Variant summary

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

The NM_004525.3(LRP2):c.4236G>C(p.Arg1412Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,046 control chromosomes in the GnomAD database, including 764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 356 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 408 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.591

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 2-169239585-C-G is Benign according to our data. Variant chr2-169239585-C-G is described in ClinVar as [Benign]. Clinvar id is 129523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169239585-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.591 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3 linkuse as main transcript	c.4236G>C	p.Arg1412Arg	synonymous_variant	26/79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 linkuse as main transcript	c.4236G>C	p.Arg1412Arg	synonymous_variant	26/78		XP_011509485.1
LRP2	XM_047444340.1 linkuse as main transcript	c.3312G>C	p.Arg1104Arg	synonymous_variant	26/79		XP_047300296.1
LRP2	XM_011511184.3 linkuse as main transcript	c.1947G>C	p.Arg649Arg	synonymous_variant	11/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.4236G>C	p.Arg1412Arg	synonymous_variant	26/79		NM_004525.3	ENSP00000496870.1		P98164

Frequencies

GnomAD3 genomes

AF:

0.0414

AC:

6303

AN:

152122

Hom.:

352

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0190

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0176

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.00444

Gnomad OTH

AF:

0.0440

GnomAD3 exomes

AF:

0.0167

AC:

4187

AN:

251400

Hom.:

170

AF XY:

0.0148

AC XY:

2010

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.00963

Gnomad ASJ exome

AF:

0.0361

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0208

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00575

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.00903

AC:

13196

AN:

1461806

Hom.:

408

Cov.:

AF XY:

0.00930

AC XY:

6760

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.137

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.0344

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0201

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.00378

Gnomad4 OTH exome

AF:

0.0173

GnomAD4 genome

AF:

0.0416

AC:

6330

AN:

152240

Hom.:

356

Cov.:

AF XY:

0.0402

AC XY:

2995

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.130

Gnomad4 AMR

AF:

0.0190

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0172

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00443

Gnomad4 OTH

AF:

0.0436

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.0463

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.00984

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

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	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

3.1

DANN

Benign

0.52

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