chr2-169276576-A-C

Variant names:

• chr2-169276576-A-C
• rs830998
• NM_004525.3:c.1772+1169T>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.1772+1169T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 152,002 control chromosomes in the GnomAD database, including 48,806 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 0.80 (48806 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.84
• Publications: 16 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.1772+1169T>G		intron_variant	Intron 13 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.1772+1169T>G		intron_variant	Intron 13 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.848+1169T>G		intron_variant	Intron 13 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.1772+1169T>G		intron_variant	Intron 13 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.1566-1338T>G		intron_variant	Intron 12 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121542 AN: 151884 Hom.: 48773 Cov.: 31

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.931

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.821

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

GnomAD4 genome AF: 0.800 AC: 121629 AN: 152002 Hom.: 48806 Cov.: 31 AF XY: 0.801 AC XY: 59487 AN XY: 74278

African (AFR) AF: 0.784 AC: 32492 AN: 41448

American (AMR) AF: 0.805 AC: 12286 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.820 AC: 2843 AN: 3468

East Asian (EAS) AF: 0.931 AC: 4800 AN: 5154

South Asian (SAS) AF: 0.706 AC: 3398 AN: 4814

European-Finnish (FIN) AF: 0.847 AC: 8951 AN: 10566

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.797 AC: 54170 AN: 67988

Other (OTH) AF: 0.817 AC: 1721 AN: 2106

Alfa AF: 0.799 Hom.: 168813

Bravo AF: 0.801

Asia WGS AF: 0.797 AC: 2768 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.18
DANN	Benign	0.62
PhyloP100		-2.8
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: rs830998; hg19: chr2-170133086;