rs199874294
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_004525.3(LRP2):c.12125G>T(p.Arg4042Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4042H) has been classified as Likely benign.
Frequency
Consequence
NM_004525.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.12125G>T | p.Arg4042Leu | missense_variant | 65/79 | ENST00000649046.1 | |
LRP2 | XM_011511183.4 | c.11996G>T | p.Arg3999Leu | missense_variant | 64/78 | ||
LRP2 | XM_047444340.1 | c.11201G>T | p.Arg3734Leu | missense_variant | 65/79 | ||
LRP2 | XM_011511184.3 | c.9836G>T | p.Arg3279Leu | missense_variant | 50/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.12125G>T | p.Arg4042Leu | missense_variant | 65/79 | NM_004525.3 | P1 | ||
LRP2 | ENST00000649153.1 | c.3026G>T | p.Arg1009Leu | missense_variant, NMD_transcript_variant | 17/30 | ||||
LRP2 | ENST00000650252.1 | c.1157G>T | p.Arg386Leu | missense_variant, NMD_transcript_variant | 10/24 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251398Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135872
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461464Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727050
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 30, 2023 | The c.12125G>T (p.R4042L) alteration is located in exon 65 (coding exon 65) of the LRP2 gene. This alteration results from a G to T substitution at nucleotide position 12125, causing the arginine (R) at amino acid position 4042 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces arginine with leucine at codon 4042 of the LRP2 protein (p.Arg4042Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with LRP2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at