chr2-169354867-G-A

Variant names:

• chr2-169354867-G-A
• rs2389557
• NM_004525.3:c.79+7454C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004525.3(LRP2):​c.79+7454C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 152,062 control chromosomes in the GnomAD database, including 19,640 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (19640 hom., cov: 33)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.899
• Publications: 14 publications found

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]

LRP2 Gene-Disease associations (from GenCC):

• Donnai-Barrow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.79+7454C>T		intron_variant	Intron 1 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.79+7454C>T		intron_variant	Intron 1 of 77		XP_011509485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.79+7454C>T		intron_variant	Intron 1 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.79+7454C>T		intron_variant	Intron 1 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76739 AN: 151946 Hom.: 19612 Cov.: 33

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.517

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.505 AC: 76827 AN: 152062 Hom.: 19640 Cov.: 33 AF XY: 0.510 AC XY: 37900 AN XY: 74338

African (AFR) AF: 0.447 AC: 18529 AN: 41474

American (AMR) AF: 0.573 AC: 8752 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1638 AN: 3470

East Asian (EAS) AF: 0.542 AC: 2801 AN: 5172

South Asian (SAS) AF: 0.592 AC: 2849 AN: 4814

European-Finnish (FIN) AF: 0.531 AC: 5617 AN: 10572

Middle Eastern (MID) AF: 0.490 AC: 143 AN: 292

European-Non Finnish (NFE) AF: 0.515 AC: 34992 AN: 67966

Other (OTH) AF: 0.520 AC: 1099 AN: 2112

Alfa AF: 0.514 Hom.: 34826

Bravo AF: 0.502

Asia WGS AF: 0.546 AC: 1900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.72
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2389557; hg19: chr2-170211377;