rs16856530

Variant names:

• chr2-169155689-T-C
• rs16856530
• NM_004525.3:c.12151+585A>G

Variant summary

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

The NM_004525.3(LRP2):​c.12151+585A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.787 in 151,742 control chromosomes in the GnomAD database, including 47,456 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 0.79 (47456 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.363
• Publications: 2 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

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

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.12151+585A>G		intron	N/A	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.12151+585A>G		intron	N/A	ENSP00000496870.1	P98164
	LRP2	ENST00000649153.1		n.3049+585A>G		intron	N/A	ENSP00000497617.1	A0A3B3IT64
	LRP2	ENST00000650252.1		n.1183+585A>G		intron	N/A	ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes AF: 0.787 AC: 119313 AN: 151624 Hom.: 47407 Cov.: 32

Gnomad AFR AF: 0.878

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.713

Gnomad MID AF: 0.856

Gnomad NFE AF: 0.760

Gnomad OTH AF: 0.782

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

GnomAD4 genome AF: 0.787 AC: 119423 AN: 151742 Hom.: 47456 Cov.: 32 AF XY: 0.785 AC XY: 58204 AN XY: 74156

African (AFR) AF: 0.878 AC: 36366 AN: 41410

American (AMR) AF: 0.803 AC: 12250 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 2541 AN: 3458

East Asian (EAS) AF: 0.494 AC: 2543 AN: 5146

South Asian (SAS) AF: 0.854 AC: 4116 AN: 4820

European-Finnish (FIN) AF: 0.713 AC: 7495 AN: 10506

Middle Eastern (MID) AF: 0.855 AC: 248 AN: 290

European-Non Finnish (NFE) AF: 0.760 AC: 51562 AN: 67848

Other (OTH) AF: 0.784 AC: 1651 AN: 2106

Alfa AF: 0.822 Hom.: 11583

Bravo AF: 0.794

Asia WGS AF: 0.721 AC: 2508 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	17
DANN	Benign	0.61
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs16856530; hg19: chr2-170012199;