rs2228168

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_004525.3(LRP2):ā€‹c.6194T>Gā€‹(p.Ile2065Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 š‘“: 0.0000014 ( 1 hom. )
Failed GnomAD Quality Control

Consequence

LRP2
NM_004525.3 missense

Scores

1
11
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.90
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.4071605).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRP2NM_004525.3 linkuse as main transcriptc.6194T>G p.Ile2065Ser missense_variant 37/79 ENST00000649046.1
LRP2XM_011511183.4 linkuse as main transcriptc.6194T>G p.Ile2065Ser missense_variant 37/78
LRP2XM_047444340.1 linkuse as main transcriptc.5270T>G p.Ile1757Ser missense_variant 37/79
LRP2XM_011511184.3 linkuse as main transcriptc.3905T>G p.Ile1302Ser missense_variant 22/64

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRP2ENST00000649046.1 linkuse as main transcriptc.6194T>G p.Ile2065Ser missense_variant 37/79 NM_004525.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
251076
Hom.:
1
AF XY:
0.0000147
AC XY:
2
AN XY:
135680
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000137
AC:
2
AN:
1461766
Hom.:
1
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Benign
-0.020
T
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.17
T;T
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
.;D
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.41
T;T
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.3
M;M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.9
.;N
REVEL
Uncertain
0.53
Sift
Benign
0.046
.;D
Sift4G
Uncertain
0.0070
.;D
Polyphen
0.54
P;P
Vest4
0.46
MutPred
0.62
Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);
MVP
0.33
MPC
0.45
ClinPred
0.74
D
GERP RS
5.9
Varity_R
0.29
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2228168; hg19: chr2-170068564; API