2-169256138-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_004525.3(LRP2):c.2738T>C(p.Met913Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
LRP2
NM_004525.3 missense
NM_004525.3 missense
Scores
2
9
3
Clinical Significance
Conservation
PhyloP100: 9.00
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 where missense usually causes diseases, LRP2
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.2738T>C | p.Met913Thr | missense_variant | 19/79 | ENST00000649046.1 | |
LRP2 | XM_011511183.4 | c.2738T>C | p.Met913Thr | missense_variant | 19/78 | ||
LRP2 | XM_047444340.1 | c.1814T>C | p.Met605Thr | missense_variant | 19/79 | ||
LRP2 | XM_011511184.3 | c.449T>C | p.Met150Thr | missense_variant | 4/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.2738T>C | p.Met913Thr | missense_variant | 19/79 | NM_004525.3 | P1 | ||
LRP2 | ENST00000443831.1 | c.2327T>C | p.Met776Thr | missense_variant | 17/23 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251124Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135704
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460810Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726726
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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 | Feb 18, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 129514). This variant has not been reported in the literature in individuals affected with LRP2-related conditions. This variant is present in population databases (rs587780384, gnomAD 0.003%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 913 of the LRP2 protein (p.Met913Thr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
P;P;P
Vest4
0.63, 0.61
MutPred
Gain of glycosylation at M913 (P = 0.0129);Gain of glycosylation at M913 (P = 0.0129);.;
MVP
0.23
MPC
0.45
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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