rs587780383
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_004525.3(LRP2):āc.2618A>Gā(p.Asn873Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000046 ( 0 hom., cov: 32)
Exomes š: 0.000041 ( 0 hom. )
Consequence
LRP2
NM_004525.3 missense
NM_004525.3 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 6.17
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP2. . Trascript score misZ 4.5094 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Stickler syndrome, Donnai-Barrow syndrome.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.2618A>G | p.Asn873Ser | missense_variant | 18/79 | ENST00000649046.1 | NP_004516.2 | |
LRP2 | XM_011511183.4 | c.2618A>G | p.Asn873Ser | missense_variant | 18/78 | XP_011509485.1 | ||
LRP2 | XM_047444340.1 | c.1694A>G | p.Asn565Ser | missense_variant | 18/79 | XP_047300296.1 | ||
LRP2 | XM_011511184.3 | c.329A>G | p.Asn110Ser | missense_variant | 3/64 | XP_011509486.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.2618A>G | p.Asn873Ser | missense_variant | 18/79 | NM_004525.3 | ENSP00000496870.1 | |||
LRP2 | ENST00000443831.1 | c.2207A>G | p.Asn736Ser | missense_variant | 16/23 | 2 | ENSP00000409813.1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152124Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250882Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135576
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GnomAD4 exome AF: 0.0000411 AC: 60AN: 1460638Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33AN XY: 726658
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 13, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 07, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 873 of the LRP2 protein (p.Asn873Ser). This variant is present in population databases (rs587780383, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with LRP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 129513). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LRP2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;T;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.
PrimateAI
Benign
T
PROVEAN
Uncertain
.;D;D
REVEL
Uncertain
Sift
Benign
.;T;T
Sift4G
Benign
.;T;T
Polyphen
B;B;B
Vest4
0.47, 0.45
MutPred
Gain of glycosylation at N873 (P = 0.0072);Gain of glycosylation at N873 (P = 0.0072);.;
MVP
0.86
MPC
0.34
ClinPred
T
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at