2-169127533-TAAAAAAAA-TAAAAA
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_004525.3(LRP2):c.*1127_*1129delTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 126 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 0)
Exomes 𝑓: 0.0079 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
LRP2
NM_004525.3 3_prime_UTR
NM_004525.3 3_prime_UTR
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -0.293
Publications
0 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 syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
- Stickler syndromeInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- intellectual disabilityInheritance: AD Classification: LIMITED Submitted by: G2P
- congenital heart diseaseInheritance: AR Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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.*1127_*1129delTTT | 3_prime_UTR | Exon 79 of 79 | NP_004516.2 | P98164 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LRP2 | ENST00000649046.1 | MANE Select | c.*1127_*1129delTTT | 3_prime_UTR | Exon 79 of 79 | ENSP00000496870.1 | P98164 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 64564Hom.: 0 Cov.: 0
GnomAD3 genomes
AF:
AC:
0
AN:
64564
Hom.:
Cov.:
0
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
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GnomAD4 exome AF: 0.00794 AC: 1AN: 126Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 72 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
126
Hom.:
AF XY:
AC XY:
0
AN XY:
72
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AC:
0
AN:
0
American (AMR)
AC:
0
AN:
0
Ashkenazi Jewish (ASJ)
AC:
0
AN:
0
East Asian (EAS)
AC:
0
AN:
0
South Asian (SAS)
AC:
0
AN:
0
European-Finnish (FIN)
AF:
AC:
1
AN:
122
Middle Eastern (MID)
AC:
0
AN:
0
European-Non Finnish (NFE)
AC:
0
AN:
0
Other (OTH)
AF:
AC:
0
AN:
4
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00 AC: 0AN: 64564Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 28236
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
64564
Hom.:
Cov.:
0
AF XY:
AC XY:
0
AN XY:
28236
African (AFR)
AF:
AC:
0
AN:
14098
American (AMR)
AF:
AC:
0
AN:
4880
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
2124
East Asian (EAS)
AF:
AC:
0
AN:
2240
South Asian (SAS)
AF:
AC:
0
AN:
1196
European-Finnish (FIN)
AF:
AC:
0
AN:
1036
Middle Eastern (MID)
AF:
AC:
0
AN:
100
European-Non Finnish (NFE)
AF:
AC:
0
AN:
37504
Other (OTH)
AF:
AC:
0
AN:
786
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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