rs376017665
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4BP6BS2
The NM_000548.5(TSC2):c.5413G>A(p.Glu1805Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000053 in 1,604,180 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1805D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.5413G>A | p.Glu1805Lys | missense_variant | 42/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.5413G>A | p.Glu1805Lys | missense_variant | 42/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000748 AC: 18AN: 240792Hom.: 0 AF XY: 0.000107 AC XY: 14AN XY: 131454
GnomAD4 exome AF: 0.0000544 AC: 79AN: 1451852Hom.: 0 Cov.: 33 AF XY: 0.0000761 AC XY: 55AN XY: 722582
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152328Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74486
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 12, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
TSC2-related condition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 20, 2023 | The TSC2 c.5413G>A variant is predicted to result in the amino acid substitution p.Glu1805Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2138600-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Tuberous sclerosis syndrome Benign:1
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 02, 2021 | This alteration is classified as 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at