rs2228168
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_004525.3(LRP2):c.6194T>G(p.Ile2065Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2065T) has been classified as Benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
LRP2
NM_004525.3 missense
NM_004525.3 missense
Scores
1
8
5
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 5.90
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 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, LRP2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.4071605).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.6194T>G | p.Ile2065Ser | missense_variant | 37/79 | ENST00000649046.1 | |
LRP2 | XM_011511183.4 | c.6194T>G | p.Ile2065Ser | missense_variant | 37/78 | ||
LRP2 | XM_047444340.1 | c.5270T>G | p.Ile1757Ser | missense_variant | 37/79 | ||
LRP2 | XM_011511184.3 | c.3905T>G | p.Ile1302Ser | missense_variant | 22/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.6194T>G | p.Ile2065Ser | missense_variant | 37/79 | NM_004525.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251076Hom.: 1 AF XY: 0.0000147 AC XY: 2AN XY: 135680
GnomAD3 exomes
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2AN: 1461766Hom.: 1 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727202
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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1461766
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727202
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ExAC
?
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2
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Polyphen
P;P
Vest4
0.46
MutPred
Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);
MVP
0.33
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