rs2075255

Positions:

• chr2-169243385-A-C
• chr2-169243385-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.3550+18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,610,366 control chromosomes in the GnomAD database, including 206,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24806 hom., cov: 31)
  • Exomes 𝑓: 0.49 (182142 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.150

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-169243385-A-C is Benign according to our data. Variant chr2-169243385-A-C is described in ClinVar as [Benign]. Clinvar id is 259414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169243385-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.3550+18T>G		intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.3550+18T>G		intron_variant			XP_011509485.1
LRP2	XM_011511184.3	c.1261+18T>G		intron_variant			XP_011509486.1
LRP2	XM_047444340.1	c.2626+18T>G		intron_variant			XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.3550+18T>G		intron_variant			NM_004525.3	ENSP00000496870	P1
LRP2	ENST00000443831.1	c.3139+18T>G		intron_variant		2		ENSP00000409813

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84540 AN: 151390 Hom.: 24756 Cov.: 31

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.753

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.556

GnomAD3 exomes AF: 0.548 AC: 137657 AN: 250986 Hom.: 39820 AF XY: 0.550 AC XY: 74604 AN XY: 135654

Gnomad AFR exome AF: 0.738

Gnomad AMR exome AF: 0.678

Gnomad ASJ exome AF: 0.571

Gnomad EAS exome AF: 0.484

Gnomad SAS exome AF: 0.749

Gnomad FIN exome AF: 0.390

Gnomad NFE exome AF: 0.468

Gnomad OTH exome AF: 0.511

GnomAD4 exome AF: 0.491 AC: 715710 AN: 1458856 Hom.: 182142 Cov.: 35 AF XY: 0.498 AC XY: 361231 AN XY: 725820

Gnomad4 AFR exome AF: 0.737

Gnomad4 AMR exome AF: 0.670

Gnomad4 ASJ exome AF: 0.554

Gnomad4 EAS exome AF: 0.461

Gnomad4 SAS exome AF: 0.743

Gnomad4 FIN exome AF: 0.393

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.515

GnomAD4 genome AF: 0.559 AC: 84649 AN: 151510 Hom.: 24806 Cov.: 31 AF XY: 0.560 AC XY: 41468 AN XY: 74040

Gnomad4 AFR AF: 0.729

Gnomad4 AMR AF: 0.606

Gnomad4 ASJ AF: 0.535

Gnomad4 EAS AF: 0.484

Gnomad4 SAS AF: 0.750

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.560

Alfa AF: 0.438 Hom.: 2146

Bravo AF: 0.580

Asia WGS AF: 0.660 AC: 2296 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Donnai-Barrow syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.13
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2075255; hg19: chr2-170099895; COSMIC: COSV104378319;