rs62171262

Positions:

• chr2-169292235-A-G

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.769+18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0639 in 1,520,040 control chromosomes in the GnomAD database, including 3,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (335 hom., cov: 31)
  • Exomes 𝑓: 0.065 (3480 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.27

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 2-169292235-A-G is Benign according to our data. Variant chr2-169292235-A-G is described in ClinVar as [Benign]. Clinvar id is 259421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169292235-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.769+18T>C		intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.769+18T>C		intron_variant			XP_011509485.1
LRP2	XM_047444340.1	c.-156+18T>C		intron_variant			XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.769+18T>C		intron_variant			NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.769+18T>C		intron_variant		2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 8259 AN: 152092 Hom.: 336 Cov.: 31

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0480

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0768

Gnomad FIN AF: 0.0825

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.0681

Gnomad OTH AF: 0.0619

GnomAD3 exomes AF: 0.0625 AC: 15690 AN: 251058 Hom.: 666 AF XY: 0.0654 AC XY: 8874 AN XY: 135678

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.0818

Gnomad FIN exome AF: 0.0796

Gnomad NFE exome AF: 0.0672

Gnomad OTH exome AF: 0.0815

GnomAD4 exome AF: 0.0650 AC: 88929 AN: 1367828 Hom.: 3480 Cov.: 21 AF XY: 0.0667 AC XY: 45757 AN XY: 686116

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.0365

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.000484

Gnomad4 SAS exome AF: 0.0856

Gnomad4 FIN exome AF: 0.0799

Gnomad4 NFE exome AF: 0.0642

Gnomad4 OTH exome AF: 0.0697

GnomAD4 genome AF: 0.0543 AC: 8259 AN: 152212 Hom.: 335 Cov.: 31 AF XY: 0.0550 AC XY: 4092 AN XY: 74416

Gnomad4 AFR AF: 0.0194

Gnomad4 AMR AF: 0.0479

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0770

Gnomad4 FIN AF: 0.0825

Gnomad4 NFE AF: 0.0681

Gnomad4 OTH AF: 0.0608

Alfa AF: 0.0786 Hom.: 121

Bravo AF: 0.0498

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Donnai-Barrow syndrome Benign:1

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	-0.84
CADD	Benign	6.2
DANN	Benign	0.64

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: rs62171262; hg19: chr2-170148745; COSMIC: COSV55570363;