2-169174407-C-A

Variant names:

• chr2-169174407-C-A
• rs2024481
• NM_004525.3:c.10769-243G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004525.3(LRP2):​c.10769-243G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 152,094 control chromosomes in the GnomAD database, including 17,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.47 (17772 hom., cov: 33)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.518
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-169174407-C-A is Benign according to our data. Variant chr2-169174407-C-A is described in ClinVar as Benign. ClinVar VariationId is 1228008.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.602 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.10769-243G>T		intron	N/A	NP_004516.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.10769-243G>T		intron	N/A	ENSP00000496870.1
	LRP2	ENST00000649153.1		n.1667-243G>T		intron	N/A	ENSP00000497617.1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71955 AN: 151978 Hom.: 17757 Cov.: 33

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.483

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

GnomAD4 genome AF: 0.474 AC: 72020 AN: 152094 Hom.: 17772 Cov.: 33 AF XY: 0.472 AC XY: 35083 AN XY: 74368

African (AFR) AF: 0.398 AC: 16511 AN: 41466

American (AMR) AF: 0.612 AC: 9362 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1568 AN: 3472

East Asian (EAS) AF: 0.105 AC: 544 AN: 5184

South Asian (SAS) AF: 0.485 AC: 2340 AN: 4828

European-Finnish (FIN) AF: 0.455 AC: 4805 AN: 10568

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35310 AN: 67966

Other (OTH) AF: 0.483 AC: 1022 AN: 2116

Alfa AF: 0.429 Hom.: 1929

Bravo AF: 0.479

Asia WGS AF: 0.352 AC: 1224 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.54
PhyloP100		-0.52
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: rs2024481; hg19: chr2-170030917;