rs2075254

Positions:

• chr2-169243389-G-A

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+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,610,778 control chromosomes in the GnomAD database, including 198,121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23015 hom., cov: 31)
  • Exomes 𝑓: 0.48 (175106 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.01

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=-0.86).
• BP6: Variant 2-169243389-G-A is Benign according to our data. Variant chr2-169243389-G-A is described in ClinVar as [Benign]. Clinvar id is 259413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169243389-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.3550+14C>T		intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.3550+14C>T		intron_variant			XP_011509485.1
LRP2	XM_011511184.3	c.1261+14C>T		intron_variant			XP_011509486.1
LRP2	XM_047444340.1	c.2626+14C>T		intron_variant			XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.3550+14C>T		intron_variant			NM_004525.3	ENSP00000496870	P1
LRP2	ENST00000443831.1	c.3139+14C>T		intron_variant		2		ENSP00000409813

Frequencies

GnomAD3 genomes AF: 0.541 AC: 81802 AN: 151314 Hom.: 22980 Cov.: 31

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.538

GnomAD3 exomes AF: 0.537 AC: 134748 AN: 251022 Hom.: 38203 AF XY: 0.539 AC XY: 73086 AN XY: 135664

Gnomad AFR exome AF: 0.697

Gnomad AMR exome AF: 0.672

Gnomad ASJ exome AF: 0.542

Gnomad EAS exome AF: 0.473

Gnomad SAS exome AF: 0.747

Gnomad FIN exome AF: 0.385

Gnomad NFE exome AF: 0.457

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.481 AC: 701907 AN: 1459344 Hom.: 175106 Cov.: 37 AF XY: 0.488 AC XY: 354563 AN XY: 726030

Gnomad4 AFR exome AF: 0.695

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.524

Gnomad4 EAS exome AF: 0.456

Gnomad4 SAS exome AF: 0.741

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.501

GnomAD4 genome AF: 0.541 AC: 81894 AN: 151434 Hom.: 23015 Cov.: 31 AF XY: 0.542 AC XY: 40130 AN XY: 73976

Gnomad4 AFR AF: 0.689

Gnomad4 AMR AF: 0.596

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.474

Gnomad4 SAS AF: 0.748

Gnomad4 FIN AF: 0.381

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.543

Alfa AF: 0.507 Hom.: 4410

Bravo AF: 0.560

Asia WGS AF: 0.647 AC: 2251 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	Apr 07, 2016	- -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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	Aug 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.9
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2075254; hg19: chr2-170099899; COSMIC: COSV104378320;