chr2-169190340-C-T

Variant names:

• chr2-169190340-C-T
• rs10210408
• NM_004525.3:c.9032+1492G>A

Variant summary

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

The NM_004525.3(LRP2):​c.9032+1492G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 152,120 control chromosomes in the GnomAD database, including 28,498 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 0.60 (28498 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.464
• Publications: 15 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.9032+1492G>A		intron_variant	Intron 48 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.9032+1492G>A		intron_variant	Intron 48 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.8108+1492G>A		intron_variant	Intron 48 of 78		XP_047300296.1
LRP2	XM_011511184.3	c.6743+1492G>A		intron_variant	Intron 33 of 63		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.9032+1492G>A		intron_variant	Intron 48 of 78		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91282 AN: 152002 Hom.: 28484 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.641

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

GnomAD4 genome AF: 0.600 AC: 91341 AN: 152120 Hom.: 28498 Cov.: 32 AF XY: 0.601 AC XY: 44678 AN XY: 74374

African (AFR) AF: 0.422 AC: 17516 AN: 41484

American (AMR) AF: 0.710 AC: 10862 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2179 AN: 3472

East Asian (EAS) AF: 0.456 AC: 2360 AN: 5176

South Asian (SAS) AF: 0.728 AC: 3513 AN: 4826

European-Finnish (FIN) AF: 0.599 AC: 6338 AN: 10582

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.683 AC: 46432 AN: 67974

Other (OTH) AF: 0.643 AC: 1356 AN: 2108

Alfa AF: 0.663 Hom.: 61665

Bravo AF: 0.598

Asia WGS AF: 0.594 AC: 2064 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.75
DANN	Benign	0.33
PhyloP100		-0.46
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: rs10210408; hg19: chr2-170046850;