chr10-43114482-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_020975.6(RET):c.1882C>T(p.Pro628Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. P628A) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1882C>T | p.Pro628Ser | missense_variant, splice_region_variant | 11/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1882C>T | p.Pro628Ser | missense_variant, splice_region_variant | 11/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000406 AC: 1AN: 246532Hom.: 0 AF XY: 0.00000748 AC XY: 1AN XY: 133748
GnomAD4 exome Cov.: 32
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74290
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2020 | 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RET-related conditions. This variant is present in population databases (rs754466051, ExAC 0.002%). This sequence change replaces proline with serine at codon 628 of the RET protein (p.Pro628Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at