rs33954745

chr2-169259162-A-G

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.2376T>C(p.Asp792=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 1,613,034 control chromosomes in the GnomAD database, including 5,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (681 hom., cov: 30)
  • Exomes 𝑓: 0.076 (4585 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.46

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=-0.48).
• BP6: Variant 2-169259162-A-G is Benign according to our data. Variant chr2-169259162-A-G is described in ClinVar as [Benign]. Clinvar id is 129509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169259162-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.2376T>C	p.Asp792=	synonymous_variant	17/79	ENST00000649046.1
LRP2	XM_011511183.4	c.2376T>C	p.Asp792=	synonymous_variant	17/78
LRP2	XM_047444340.1	c.1452T>C	p.Asp484=	synonymous_variant	17/79
LRP2	XM_011511184.3	c.87T>C	p.Asp29=	synonymous_variant	2/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.2376T>C	p.Asp792=	synonymous_variant	17/79		NM_004525.3	P1
LRP2	ENST00000443831.1	c.1965T>C	p.Asp655=	synonymous_variant	15/23	2

Frequencies

GnomAD3 genomes AF: 0.0892 AC: 13551 AN: 151912 Hom.: 678 Cov.: 30

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0896

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.0460

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0800

Gnomad OTH AF: 0.0994

GnomAD3 exomes AF: 0.0696 AC: 17457 AN: 250904 Hom.: 751 AF XY: 0.0696 AC XY: 9441 AN XY: 135594

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0580

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.00179

Gnomad SAS exome AF: 0.0555

Gnomad FIN exome AF: 0.0337

Gnomad NFE exome AF: 0.0793

Gnomad OTH exome AF: 0.0812

GnomAD4 exome AF: 0.0756 AC: 110517 AN: 1461004 Hom.: 4585 Cov.: 34 AF XY: 0.0754 AC XY: 54827 AN XY: 726848

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.0611

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.00169

Gnomad4 SAS exome AF: 0.0557

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0793

Gnomad4 OTH exome AF: 0.0792

GnomAD4 genome AF: 0.0893 AC: 13582 AN: 152030 Hom.: 681 Cov.: 30 AF XY: 0.0865 AC XY: 6429 AN XY: 74306

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0895

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.00233

Gnomad4 SAS AF: 0.0459

Gnomad4 FIN AF: 0.0298

Gnomad4 NFE AF: 0.0800

Gnomad4 OTH AF: 0.0984

Alfa AF: 0.0898 Hom.: 264

Bravo AF: 0.0957

Asia WGS AF: 0.0510 AC: 179 AN: 3478

EpiCase AF: 0.0831

EpiControl AF: 0.0846

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	8.1
Dann	Benign	0.57

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: rs33954745; hg19: chr2-170115672; COSMIC: COSV55552097;