rs140658743
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7
The NM_020975.6(RET):c.2298G>A(p.Pro766=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,860 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). Synonymous variant affecting the same amino acid position (i.e. P766P) has been classified as Likely benign.
Frequency
Consequence
NM_020975.6 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.2298G>A | p.Pro766= | synonymous_variant | 13/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.2298G>A | p.Pro766= | synonymous_variant | 13/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251178Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135824
GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461664Hom.: 0 Cov.: 29 AF XY: 0.0000633 AC XY: 46AN XY: 727124
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2021 | In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with Hirschsprung disease (Jannot et al., 2012); This variant is associated with the following publications: (PMID: 28873162, 22395866) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | RET: BP4, BP7 - |
Multiple endocrine neoplasia type 2B Benign:2
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 12, 2016 | - - |
Multiple endocrine neoplasia type 2A Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 12, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 2023 | 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 07, 2022 | - - |
Multiple endocrine neoplasia, type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at