rs33954745
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_004525.3(LRP2):āc.2376T>Cā(p.Asp792=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 1,613,034 control chromosomes in the GnomAD database, including 5,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.089 ( 681 hom., cov: 30)
Exomes š: 0.076 ( 4585 hom. )
Consequence
LRP2
NM_004525.3 synonymous
NM_004525.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.46
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 -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 2-169259162-A-G is Benign according to our data. Variant chr2-169259162-A-G is described in ClinVar as [Benign]. Clinvar id is 129509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169259162-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=1.46 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.2376T>C | p.Asp792= | synonymous_variant | 17/79 | ENST00000649046.1 | |
LRP2 | XM_011511183.4 | c.2376T>C | p.Asp792= | synonymous_variant | 17/78 | ||
LRP2 | XM_047444340.1 | c.1452T>C | p.Asp484= | synonymous_variant | 17/79 | ||
LRP2 | XM_011511184.3 | c.87T>C | p.Asp29= | synonymous_variant | 2/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.2376T>C | p.Asp792= | synonymous_variant | 17/79 | NM_004525.3 | P1 | ||
LRP2 | ENST00000443831.1 | c.1965T>C | p.Asp655= | synonymous_variant | 15/23 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0892 AC: 13551AN: 151912Hom.: 678 Cov.: 30
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GnomAD3 exomes AF: 0.0696 AC: 17457AN: 250904Hom.: 751 AF XY: 0.0696 AC XY: 9441AN XY: 135594
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GnomAD4 exome AF: 0.0756 AC: 110517AN: 1461004Hom.: 4585 Cov.: 34 AF XY: 0.0754 AC XY: 54827AN XY: 726848
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GnomAD4 genome AF: 0.0893 AC: 13582AN: 152030Hom.: 681 Cov.: 30 AF XY: 0.0865 AC XY: 6429AN XY: 74306
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
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. - |
Donnai-Barrow syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
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. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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