2-169301946-C-T

Variant names:

• chr2-169301946-C-T
• rs700550
• NM_004525.3:c.427+5335G>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.427+5335G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.658 in 151,944 control chromosomes in the GnomAD database, including 33,641 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 0.66 (33641 hom., cov: 30)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277
• Publications: 5 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.427+5335G>A		intron	N/A	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.427+5335G>A		intron	N/A	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.427+5335G>A		intron	N/A	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99798 AN: 151826 Hom.: 33591 Cov.: 30

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.634

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

GnomAD4 genome AF: 0.658 AC: 99907 AN: 151944 Hom.: 33641 Cov.: 30 AF XY: 0.661 AC XY: 49078 AN XY: 74280

African (AFR) AF: 0.785 AC: 32524 AN: 41452

American (AMR) AF: 0.719 AC: 10967 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1963 AN: 3470

East Asian (EAS) AF: 0.799 AC: 4136 AN: 5176

South Asian (SAS) AF: 0.673 AC: 3239 AN: 4812

European-Finnish (FIN) AF: 0.597 AC: 6296 AN: 10546

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38778 AN: 67924

Other (OTH) AF: 0.634 AC: 1339 AN: 2112

Alfa AF: 0.603 Hom.: 53121

Bravo AF: 0.673

Asia WGS AF: 0.758 AC: 2637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.9
DANN	Benign	0.42
PhyloP100		0.28
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: rs700550; hg19: chr2-170158456;