chr2-169286682-G-C

Variant names:

• chr2-169286682-G-C
• rs831016
• NM_004525.3:c.1042+2344C>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.1042+2344C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 151,862 control chromosomes in the GnomAD database, including 17,805 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 0.47 (17805 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.116
• 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: 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.1042+2344C>G		intron_variant	Intron 9 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.1042+2344C>G		intron_variant	Intron 9 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.118+2344C>G		intron_variant	Intron 9 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.1042+2344C>G		intron_variant	Intron 9 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.1042+2344C>G		intron_variant	Intron 9 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71794 AN: 151744 Hom.: 17772 Cov.: 32

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.473 AC: 71870 AN: 151862 Hom.: 17805 Cov.: 32 AF XY: 0.470 AC XY: 34888 AN XY: 74200

African (AFR) AF: 0.615 AC: 25448 AN: 41398

American (AMR) AF: 0.526 AC: 8038 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1570 AN: 3470

East Asian (EAS) AF: 0.440 AC: 2270 AN: 5154

South Asian (SAS) AF: 0.331 AC: 1593 AN: 4808

European-Finnish (FIN) AF: 0.382 AC: 4025 AN: 10528

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27508 AN: 67924

Other (OTH) AF: 0.435 AC: 916 AN: 2106

Alfa AF: 0.437 Hom.: 1830

Bravo AF: 0.494

Asia WGS AF: 0.413 AC: 1436 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.2
DANN	Benign	0.68
PhyloP100		0.12
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: rs831016; hg19: chr2-170143192;