rs753060862
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000548.5(TSC2):c.4613C>A(p.Pro1538Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P1538L) has been classified as Likely benign.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.4613C>A | p.Pro1538Gln | missense_variant | 36/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.4613C>A | p.Pro1538Gln | missense_variant | 36/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250006Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135688
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460412Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726510
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | This missense variant replaces proline with glutamine at codon 1538 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC2-related disorders in the literature. This variant has been identified in 2/250006 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Isolated focal cortical dysplasia type II Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 11, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2023 | The p.P1538Q variant (also known as c.4613C>A), located in coding exon 35 of the TSC2 gene, results from a C to A substitution at nucleotide position 4613. The proline at codon 1538 is replaced by glutamine, an amino acid with 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Tuberous sclerosis 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at