rs141180155

chr2-169271049-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004525.3(LRP2):c.2175C>T(p.Thr725=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,154 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (10 hom., cov: 31)
  • Exomes 𝑓: 0.011 (115 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.548

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=-0.67).
• BP6: Variant 2-169271049-G-A is Benign according to our data. Variant chr2-169271049-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.548 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00793 (1206/152124) while in subpopulation NFE AF= 0.0133 (903/67980). AF 95% confidence interval is 0.0126. There are 10 homozygotes in gnomad4. There are 577 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.2175C>T	p.Thr725=	synonymous_variant	16/79	ENST00000649046.1
LRP2	XM_011511183.4	c.2175C>T	p.Thr725=	synonymous_variant	16/78
LRP2	XM_047444340.1	c.1251C>T	p.Thr417=	synonymous_variant	16/79
LRP2	XM_011511184.3	c.31+621C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.2175C>T	p.Thr725=	synonymous_variant	16/79		NM_004525.3	P1
LRP2	ENST00000443831.1	c.1909+1878C>T		intron_variant		2
LRP2	ENST00000493501.1	n.518C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.00793 AC: 1206 AN: 152006 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00794

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00435

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00804 AC: 2016 AN: 250838 Hom.: 15 AF XY: 0.00786 AC XY: 1065 AN XY: 135550

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00421

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.00851

GnomAD4 exome AF: 0.0112 AC: 16309 AN: 1461030 Hom.: 115 Cov.: 32 AF XY: 0.0109 AC XY: 7950 AN XY: 726826

Gnomad4 AFR exome AF: 0.00168

Gnomad4 AMR exome AF: 0.00594

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00472

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.00979

GnomAD4 genome AF: 0.00793 AC: 1206 AN: 152124 Hom.: 10 Cov.: 31 AF XY: 0.00776 AC XY: 577 AN XY: 74360

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00793

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00435

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0103 Hom.: 6

Bravo AF: 0.00808

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LRP2: BP4, BP7, BS1, BS2 -

not specified Benign:2

Likely 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	-0.67
Cadd	Benign	5.6
Dann	Benign	0.60

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: rs141180155; hg19: chr2-170127559; COSMIC: COSV55569730;