2-169280981-G-C

Variant names:

• chr2-169280981-G-C
• rs831006
• NM_004525.3:c.1172-462C>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.1172-462C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 152,028 control chromosomes in the GnomAD database, including 24,095 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 0.55 (24095 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.1172-462C>G		intron_variant	Intron 10 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.1172-462C>G		intron_variant	Intron 10 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.248-462C>G		intron_variant	Intron 10 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.1172-462C>G		intron_variant	Intron 10 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.1172-462C>G		intron_variant	Intron 10 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83040 AN: 151912 Hom.: 24101 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.889

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.583

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

GnomAD4 genome AF: 0.546 AC: 83047 AN: 152028 Hom.: 24095 Cov.: 32 AF XY: 0.549 AC XY: 40842 AN XY: 74326

African (AFR) AF: 0.346 AC: 14322 AN: 41448

American (AMR) AF: 0.642 AC: 9804 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2000 AN: 3466

East Asian (EAS) AF: 0.889 AC: 4608 AN: 5184

South Asian (SAS) AF: 0.516 AC: 2489 AN: 4820

European-Finnish (FIN) AF: 0.651 AC: 6875 AN: 10556

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 41001 AN: 67952

Other (OTH) AF: 0.581 AC: 1230 AN: 2116

Alfa AF: 0.560 Hom.: 2937

Bravo AF: 0.543

Asia WGS AF: 0.648 AC: 2252 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.090
DANN	Benign	0.51
PhyloP100		-1.1
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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs831006; hg19: chr2-170137491;