rs830994

chr2-169273018-G-Achr2-169273018-G-Cchr2-169273018-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004525.3(LRP2):c.2025C>T(p.Val675=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,364 control chromosomes in the GnomAD database, including 341,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29403 hom., cov: 33)
  • Exomes 𝑓: 0.65 (312379 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0940

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 2-169273018-G-A is Benign according to our data. Variant chr2-169273018-G-A is described in ClinVar as [Benign]. Clinvar id is 129507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169273018-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.094 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.2025C>T	p.Val675=	synonymous_variant	15/79	ENST00000649046.1
LRP2	XM_011511183.4	c.2025C>T	p.Val675=	synonymous_variant	15/78
LRP2	XM_047444340.1	c.1101C>T	p.Val367=	synonymous_variant	15/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.2025C>T	p.Val675=	synonymous_variant	15/79		NM_004525.3	P1
LRP2	ENST00000443831.1	c.1818C>T	p.Val606=	synonymous_variant	14/23	2
LRP2	ENST00000493501.1	n.368C>T		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93399 AN: 151888 Hom.: 29400 Cov.: 33

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.657

GnomAD3 exomes AF: 0.628 AC: 157447 AN: 250798 Hom.: 51223 AF XY: 0.628 AC XY: 85134 AN XY: 135510

Gnomad AFR exome AF: 0.517

Gnomad AMR exome AF: 0.480

Gnomad ASJ exome AF: 0.708

Gnomad EAS exome AF: 0.917

Gnomad SAS exome AF: 0.504

Gnomad FIN exome AF: 0.669

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.648

GnomAD4 exome AF: 0.650 AC: 949919 AN: 1461358 Hom.: 312379 Cov.: 54 AF XY: 0.647 AC XY: 470252 AN XY: 727002

Gnomad4 AFR exome AF: 0.526

Gnomad4 AMR exome AF: 0.491

Gnomad4 ASJ exome AF: 0.706

Gnomad4 EAS exome AF: 0.858

Gnomad4 SAS exome AF: 0.506

Gnomad4 FIN exome AF: 0.672

Gnomad4 NFE exome AF: 0.661

Gnomad4 OTH exome AF: 0.654

GnomAD4 genome AF: 0.615 AC: 93432 AN: 152006 Hom.: 29403 Cov.: 33 AF XY: 0.611 AC XY: 45415 AN XY: 74292

Gnomad4 AFR AF: 0.519

Gnomad4 AMR AF: 0.541

Gnomad4 ASJ AF: 0.701

Gnomad4 EAS AF: 0.900

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.665

Gnomad4 NFE AF: 0.661

Gnomad4 OTH AF: 0.655

Alfa AF: 0.640 Hom.: 33495

Bravo AF: 0.611

Asia WGS AF: 0.649 AC: 2256 AN: 3476

EpiCase AF: 0.677

EpiControl AF: 0.682

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

Donnai-Barrow syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	5.8
Dann	Benign	0.72

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

Other links and lift over

dbSNP: rs830994; hg19: chr2-170129528;