rs830995

chr2-169273126-A-Gchr2-169273126-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004525.3(LRP2):c.1976-59T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,600,436 control chromosomes in the GnomAD database, including 398,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.69 (36325 hom., cov: 31)
  • Exomes 𝑓: 0.70 (362492 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.16

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-169273126-A-G is Benign according to our data. Variant chr2-169273126-A-G is described in ClinVar as [Benign]. Clinvar id is 1232462.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.1976-59T>C		intron_variant		ENST00000649046.1
LRP2	XM_011511183.4	c.1976-59T>C		intron_variant
LRP2	XM_047444340.1	c.1052-59T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.1976-59T>C		intron_variant			NM_004525.3	P1
LRP2	ENST00000443831.1	c.1769-59T>C		intron_variant		2
LRP2	ENST00000493501.1	n.319-59T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104494 AN: 151946 Hom.: 36312 Cov.: 31

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.907

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.720

GnomAD4 exome AF: 0.704 AC: 1020264 AN: 1448372 Hom.: 362492 AF XY: 0.701 AC XY: 505855 AN XY: 721500

Gnomad4 AFR exome AF: 0.648

Gnomad4 AMR exome AF: 0.527

Gnomad4 ASJ exome AF: 0.765

Gnomad4 EAS exome AF: 0.873

Gnomad4 SAS exome AF: 0.559

Gnomad4 FIN exome AF: 0.742

Gnomad4 NFE exome AF: 0.715

Gnomad4 OTH exome AF: 0.708

GnomAD4 genome AF: 0.688 AC: 104549 AN: 152064 Hom.: 36325 Cov.: 31 AF XY: 0.684 AC XY: 50876 AN XY: 74338

Gnomad4 AFR AF: 0.643

Gnomad4 AMR AF: 0.591

Gnomad4 ASJ AF: 0.760

Gnomad4 EAS AF: 0.908

Gnomad4 SAS AF: 0.559

Gnomad4 FIN AF: 0.739

Gnomad4 NFE AF: 0.715

Gnomad4 OTH AF: 0.717

Alfa AF: 0.695 Hom.: 16113

Bravo AF: 0.682

Asia WGS AF: 0.697 AC: 2425 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.7
Dann	Benign	0.55

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: rs830995; hg19: chr2-170129636;