rs11886219

Positions:

• chr2-169213838-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004525.3(LRP2):​c.5859A>G​(p.Arg1953Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,613,164 control chromosomes in the GnomAD database, including 9,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (3900 hom., cov: 32)
  • Exomes 𝑓: 0.061 (5384 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.572

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-169213838-T-C is Benign according to our data. Variant chr2-169213838-T-C is described in ClinVar as [Benign]. Clinvar id is 129530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169213838-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.572 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.5859A>G	p.Arg1953Arg	synonymous_variant	36/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.5859A>G	p.Arg1953Arg	synonymous_variant	36/78		XP_011509485.1
LRP2	XM_047444340.1	c.4935A>G	p.Arg1645Arg	synonymous_variant	36/79		XP_047300296.1
LRP2	XM_011511184.3	c.3570A>G	p.Arg1190Arg	synonymous_variant	21/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.5859A>G	p.Arg1953Arg	synonymous_variant	36/79		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23574 AN: 152056 Hom.: 3894 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0916

Gnomad ASJ AF: 0.0808

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0554

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.0721 AC: 17968 AN: 249104 Hom.: 1865 AF XY: 0.0658 AC XY: 8870 AN XY: 134866

Gnomad AFR exome AF: 0.430

Gnomad AMR exome AF: 0.0500

Gnomad ASJ exome AF: 0.0830

Gnomad EAS exome AF: 0.00136

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0254

Gnomad NFE exome AF: 0.0533

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0614 AC: 89727 AN: 1460990 Hom.: 5384 Cov.: 32 AF XY: 0.0603 AC XY: 43813 AN XY: 726816

Gnomad4 AFR exome AF: 0.431

Gnomad4 AMR exome AF: 0.0561

Gnomad4 ASJ exome AF: 0.0783

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0486

Gnomad4 FIN exome AF: 0.0263

Gnomad4 NFE exome AF: 0.0542

Gnomad4 OTH exome AF: 0.0754

GnomAD4 genome AF: 0.155 AC: 23617 AN: 152174 Hom.: 3900 Cov.: 32 AF XY: 0.149 AC XY: 11114 AN XY: 74404

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.0914

Gnomad4 ASJ AF: 0.0808

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.0554

Gnomad4 OTH AF: 0.125

Alfa AF: 0.0874 Hom.: 1418

Bravo AF: 0.174

Asia WGS AF: 0.0630 AC: 221 AN: 3476

EpiCase AF: 0.0525

EpiControl AF: 0.0508

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -

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	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	-0.57
CADD	Benign	3.1
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs11886219; hg19: chr2-170070348; COSMIC: COSV55553488;