2-169207247-T-G
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1
The NM_004525.3(LRP2):āc.6473A>Cā(p.Asn2158Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,612,820 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0015 ( 1 hom., cov: 32)
Exomes š: 0.00020 ( 1 hom. )
Consequence
LRP2
NM_004525.3 missense
NM_004525.3 missense
Scores
9
6
4
Clinical Significance
Conservation
PhyloP100: 7.99
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 -8 ACMG points.
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=0.017685115).
BP6
Variant 2-169207247-T-G is Benign according to our data. Variant chr2-169207247-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 591104.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00149 (227/152250) while in subpopulation AFR AF= 0.00479 (199/41546). AF 95% confidence interval is 0.00424. There are 1 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.6473A>C | p.Asn2158Thr | missense_variant | 39/79 | ENST00000649046.1 | NP_004516.2 | |
LRP2 | XM_011511183.4 | c.6473A>C | p.Asn2158Thr | missense_variant | 39/78 | XP_011509485.1 | ||
LRP2 | XM_047444340.1 | c.5549A>C | p.Asn1850Thr | missense_variant | 39/79 | XP_047300296.1 | ||
LRP2 | XM_011511184.3 | c.4184A>C | p.Asn1395Thr | missense_variant | 24/64 | XP_011509486.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.6473A>C | p.Asn2158Thr | missense_variant | 39/79 | NM_004525.3 | ENSP00000496870 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00148 AC: 225AN: 152132Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000492 AC: 122AN: 247810Hom.: 0 AF XY: 0.000409 AC XY: 55AN XY: 134386
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GnomAD4 exome AF: 0.000203 AC: 296AN: 1460570Hom.: 1 Cov.: 32 AF XY: 0.000190 AC XY: 138AN XY: 726672
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GnomAD4 genome AF: 0.00149 AC: 227AN: 152250Hom.: 1 Cov.: 32 AF XY: 0.00157 AC XY: 117AN XY: 74432
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Uncertain significance, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27527004, 26934580, 27377421, 23675308) - |
LRP2-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 31, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D
REVEL
Pathogenic
Sift
Uncertain
.;D
Sift4G
Uncertain
.;D
Polyphen
D;D
Vest4
0.90
MVP
0.81
MPC
0.87
ClinPred
T
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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