10-43077257-C-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting
The NM_020975.6(RET):c.-2C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000752 in 1,503,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_020975.6 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.-2C>A | 5_prime_UTR_variant | Exon 1 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000467 AC: 71AN: 151942Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.0000478 AC: 5AN: 104494Hom.: 0 AF XY: 0.0000172 AC XY: 1AN XY: 58064
GnomAD4 exome AF: 0.0000311 AC: 42AN: 1350980Hom.: 0 Cov.: 30 AF XY: 0.0000375 AC XY: 25AN XY: 666264
GnomAD4 genome AF: 0.000467 AC: 71AN: 152050Hom.: 0 Cov.: 35 AF XY: 0.000538 AC XY: 40AN XY: 74356
ClinVar
Submissions by phenotype
not specified Uncertain:1
The c.-2C>A variant in RET has not been previously reported in individuals with pulmonary disease and data from large population studies is insufficient to asse ss the frequency of this variant. Computational prediction tools and conservatio n analysis are limited or unavailable for this variant. This variant is located in the 5' UTR and is part of the translation initiation (Kozak) sequence, but it s effect on translation is unknown. In summary, the clinical significance of the c.-2C>A variant is uncertain. -
Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Uncertain:1
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not provided Uncertain:1
Nucleotide substitution 2 base pairs upstream of the ATG translational start site in the 5' untranslated region (UTR); Nucleotide substitution has no predicted effect on splicing and is not conserved across species; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
RET-related disorder Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at