rs76488092
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004525.3(LRP2):c.11759-5T>G variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00256 in 1,614,108 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.014 ( 47 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 39 hom. )
Consequence
LRP2
NM_004525.3 splice_region, splice_polypyrimidine_tract, intron
NM_004525.3 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.5201
2
Clinical Significance
Conservation
PhyloP100: 4.68
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
?
Variant 2-169162605-A-C is Benign according to our data. Variant chr2-169162605-A-C is described in ClinVar as [Benign]. Clinvar id is 129496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2149/152358) while in subpopulation AFR AF= 0.048 (1994/41572). AF 95% confidence interval is 0.0462. There are 47 homozygotes in gnomad4. There are 997 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 47 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.11759-5T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000649046.1 | |||
LRP2 | XM_011511183.4 | c.11630-5T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
LRP2 | XM_011511184.3 | c.9470-5T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
LRP2 | XM_047444340.1 | c.10835-5T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.11759-5T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | NM_004525.3 | P1 | ||||
LRP2 | ENST00000649153.1 | c.2659-5T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant | ||||||
LRP2 | ENST00000650252.1 | c.791-5T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0141 AC: 2140AN: 152240Hom.: 47 Cov.: 33
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GnomAD3 exomes AF: 0.00377 AC: 948AN: 251196Hom.: 15 AF XY: 0.00289 AC XY: 392AN XY: 135746
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GnomAD4 exome AF: 0.00136 AC: 1983AN: 1461750Hom.: 39 Cov.: 32 AF XY: 0.00117 AC XY: 850AN XY: 727178
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GnomAD4 genome ? AF: 0.0141 AC: 2149AN: 152358Hom.: 47 Cov.: 33 AF XY: 0.0134 AC XY: 997AN XY: 74514
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 04, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Donnai-Barrow syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not specified Benign:1
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at