rs1990842

Variant names:

• chr2-169351525-A-C
• rs1990842
• NM_004525.3:c.79+10796T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-169351525-A-C
• chr2-169351525-A-T

Variant summary

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

The NM_004525.3(LRP2):​c.79+10796T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 152,032 control chromosomes in the GnomAD database, including 6,818 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 0.29 (6818 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0350
• Publications: 10 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.79+10796T>G		intron_variant	Intron 1 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.79+10796T>G		intron_variant	Intron 1 of 77		XP_011509485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.79+10796T>G		intron_variant	Intron 1 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.79+10796T>G		intron_variant	Intron 1 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44534 AN: 151914 Hom.: 6829 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.295

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

GnomAD4 genome AF: 0.293 AC: 44527 AN: 152032 Hom.: 6818 Cov.: 32 AF XY: 0.294 AC XY: 21844 AN XY: 74334

African (AFR) AF: 0.234 AC: 9702 AN: 41478

American (AMR) AF: 0.248 AC: 3786 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 857 AN: 3468

East Asian (EAS) AF: 0.461 AC: 2374 AN: 5148

South Asian (SAS) AF: 0.218 AC: 1052 AN: 4824

European-Finnish (FIN) AF: 0.390 AC: 4122 AN: 10582

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21659 AN: 67950

Other (OTH) AF: 0.291 AC: 615 AN: 2114

Alfa AF: 0.304 Hom.: 4408

Bravo AF: 0.284

Asia WGS AF: 0.287 AC: 997 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.44
DANN	Benign	0.30
PhyloP100		-0.035
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: rs1990842; hg19: chr2-170208035;