16-2071609-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000548.5(TSC2):c.1939G>C(p.Asp647His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D647N) 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_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.1939G>C | p.Asp647His | missense_variant | 18/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.1939G>C | p.Asp647His | missense_variant | 18/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2021 | This variant has not been reported in the literature in individuals affected with TSC2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 647 of the TSC2 protein (p.Asp647His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.