rs869320638
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_002336.3(LRP6):c.1406C>T(p.Pro469Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002336.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP6 | NM_002336.3 | c.1406C>T | p.Pro469Leu | missense_variant | 7/23 | ENST00000261349.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP6 | ENST00000261349.9 | c.1406C>T | p.Pro469Leu | missense_variant | 7/23 | 1 | NM_002336.3 | P1 | |
LRP6 | ENST00000543091.1 | c.1406C>T | p.Pro469Leu | missense_variant | 7/23 | 1 | |||
LRP6 | ENST00000538239.5 | c.1001C>T | p.Pro334Leu | missense_variant, NMD_transcript_variant | 6/24 | 1 | |||
BCL2L14 | ENST00000298566.2 | c.*25-7356G>A | intron_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151896Hom.: 0 Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151896Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74190
ClinVar
Submissions by phenotype
Tooth agenesis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Mar 10, 2016 | - - |
Tooth agenesis, selective, 7 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Prosthodontics, Peking University School and Hospital of Stomatology | Feb 19, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 28, 2022 | This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 225150). This missense change has been observed in individual(s) with tooth agenesis (PMID: 26963285). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 469 of the LRP6 protein (p.Pro469Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at