rs2239602

Variant names:

• chr2-169168830-C-T
• rs2239602
• NM_004525.3:c.11498-154G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.11498-154G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.906 in 152,276 control chromosomes in the GnomAD database, including 62,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.91 (62638 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.107
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 2-169168830-C-T is Benign according to our data. Variant chr2-169168830-C-T is described in ClinVar as Benign. ClinVar VariationId is 1245516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.942 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.11498-154G>A		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.11498-154G>A		intron	N/A	ENSP00000496870.1	P98164
	LRP2	ENST00000649153.1		n.2396-154G>A		intron	N/A	ENSP00000497617.1	A0A3B3IT64
	LRP2	ENST00000650252.1		n.530-154G>A		intron	N/A	ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes AF: 0.906 AC: 137834 AN: 152158 Hom.: 62582 Cov.: 32

Gnomad AFR AF: 0.950

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.927

Gnomad ASJ AF: 0.911

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.915

Gnomad FIN AF: 0.850

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.895

Gnomad OTH AF: 0.915

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

GnomAD4 genome AF: 0.906 AC: 137949 AN: 152276 Hom.: 62638 Cov.: 32 AF XY: 0.903 AC XY: 67273 AN XY: 74470

African (AFR) AF: 0.950 AC: 39470 AN: 41552

American (AMR) AF: 0.927 AC: 14195 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.911 AC: 3159 AN: 3466

East Asian (EAS) AF: 0.737 AC: 3808 AN: 5168

South Asian (SAS) AF: 0.914 AC: 4410 AN: 4824

European-Finnish (FIN) AF: 0.850 AC: 9016 AN: 10608

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.895 AC: 60855 AN: 68030

Other (OTH) AF: 0.916 AC: 1938 AN: 2116

Alfa AF: 0.901 Hom.: 115125

Bravo AF: 0.909

Asia WGS AF: 0.859 AC: 2987 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.75
DANN	Benign	0.57
PhyloP100		0.11
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: rs2239602; hg19: chr2-170025340;