chr16-2086743-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000548.5(TSC2):c.4861A>T(p.Ile1621Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,308 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1621V) 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_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.4861A>T | p.Ile1621Phe | missense_variant | 38/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.4861A>T | p.Ile1621Phe | missense_variant | 38/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458308Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725458
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1621 of the TSC2 protein (p.Ile1621Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 28659645; Invitae). ClinVar contains an entry for this variant (Variation ID: 535960). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at