rs6733122

Variant names:

• chr2-169143205-A-G
• rs6733122
• NM_004525.3:c.12989-412T>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.12989-412T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 152,146 control chromosomes in the GnomAD database, including 40,061 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 0.72 (40061 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560
• Publications: 4 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.12989-412T>C		intron_variant	Intron 70 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.12860-412T>C		intron_variant	Intron 69 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.12065-412T>C		intron_variant	Intron 70 of 78		XP_047300296.1
LRP2	XM_011511184.3	c.10700-412T>C		intron_variant	Intron 55 of 63		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.12989-412T>C		intron_variant	Intron 70 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000649153.1	n.3887-412T>C		intron_variant	Intron 22 of 29			ENSP00000497617.1
LRP2	ENST00000650252.1	n.*700-412T>C		intron_variant	Intron 15 of 23			ENSP00000496887.1

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109667 AN: 152028 Hom.: 40041 Cov.: 32

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.750

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.857

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.730

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

GnomAD4 genome AF: 0.721 AC: 109739 AN: 152146 Hom.: 40061 Cov.: 32 AF XY: 0.721 AC XY: 53641 AN XY: 74388

African (AFR) AF: 0.636 AC: 26392 AN: 41474

American (AMR) AF: 0.757 AC: 11572 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2379 AN: 3470

East Asian (EAS) AF: 0.470 AC: 2432 AN: 5178

South Asian (SAS) AF: 0.857 AC: 4134 AN: 4826

European-Finnish (FIN) AF: 0.716 AC: 7581 AN: 10588

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52778 AN: 68000

Other (OTH) AF: 0.730 AC: 1544 AN: 2114

Alfa AF: 0.751 Hom.: 9108

Bravo AF: 0.717

Asia WGS AF: 0.679 AC: 2363 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.66
DANN	Benign	0.65
PhyloP100		0.056
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: rs6733122; hg19: chr2-169999715;