rs766442736
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000548.5(TSC2):c.2246G>A(p.Arg749Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R749W) has been classified as Likely benign.
Frequency
Consequence
NM_000548.5 missense
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 |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.2246G>A | p.Arg749Gln | missense_variant | 21/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.2246G>A | p.Arg749Gln | missense_variant | 21/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250968Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135812
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461262Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726900
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
Tuberous sclerosis syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 08, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Tuberous sclerosis 2 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2018 | p.Arg749Gln (CGG>CAG): c.2246 G>A in exon 21 in the TSC2 gene (NM_000548.3). The R749Q variant in the TSC2 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R749Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R749Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in vertebrates. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (L737P; S758F) have been reported in association with tuberous sclerosis, supporting the functional importance of this region of the protein. We interpret R749Q as a variant of unknown significance. The variant is found in TSC2 panel(s). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2024 | The p.R749Q variant (also known as c.2246G>A), located in coding exon 20 of the TSC2 gene, results from a G to A substitution at nucleotide position 2246. The arginine at codon 749 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at