rs10490131

Variant names:

• chr2-169194657-A-G
• rs10490131
• NM_004525.3:c.8699-765T>C

Variant summary

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

The NM_004525.3(LRP2):​c.8699-765T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 151,706 control chromosomes in the GnomAD database, including 1,571 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 0.13 (1571 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• 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: 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.8699-765T>C		intron_variant	Intron 46 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.8699-765T>C		intron_variant	Intron 46 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.7775-765T>C		intron_variant	Intron 46 of 78		XP_047300296.1
LRP2	XM_011511184.3	c.6410-765T>C		intron_variant	Intron 31 of 63		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.8699-765T>C		intron_variant	Intron 46 of 78		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19037 AN: 151594 Hom.: 1574 Cov.: 31

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.158

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

GnomAD4 genome AF: 0.125 AC: 19029 AN: 151706 Hom.: 1571 Cov.: 31 AF XY: 0.126 AC XY: 9333 AN XY: 74084

African (AFR) AF: 0.0308 AC: 1276 AN: 41414

American (AMR) AF: 0.111 AC: 1701 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 620 AN: 3460

East Asian (EAS) AF: 0.359 AC: 1840 AN: 5126

South Asian (SAS) AF: 0.225 AC: 1079 AN: 4804

European-Finnish (FIN) AF: 0.143 AC: 1488 AN: 10424

Middle Eastern (MID) AF: 0.207 AC: 60 AN: 290

European-Non Finnish (NFE) AF: 0.155 AC: 10519 AN: 67906

Other (OTH) AF: 0.160 AC: 337 AN: 2106

Alfa AF: 0.146 Hom.: 2849

Bravo AF: 0.119

Asia WGS AF: 0.249 AC: 862 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.0
DANN	Benign	0.81
PhyloP100		2.3
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: rs10490131; hg19: chr2-170051167;