chr16-2084715-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000548.5(TSC2):c.4493G>C(p.Ser1498Thr) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1498N) has been classified as Uncertain significance.
Frequency
Consequence
NM_000548.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.4493G>C | p.Ser1498Thr | missense_variant, splice_region_variant | 34/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.4493G>C | p.Ser1498Thr | missense_variant, splice_region_variant | 34/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 08, 2021 | ACMG categories: PS2,PM1,PM2,PP3,BP1 - |
TSC2-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 26, 2022 | The TSC2 c.4493G>C variant is predicted to result in the amino acid substitution p.Ser1498Thr. This variant occurs at the last nucleotide position of exon 34 and is predicted to alter splicing based on available splicing prediction programs (Alamut Visual v2.11). This variant has been reported in an individual with tuberous sclerosis complex (TSC) (Zhang et al. 2014. PubMed ID: 25449086). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Alternate variants affecting the same amino acid (p.Ser1498Arg and p.Ser1498Asn) have been reported de novo in an individual with TSC (Table 2, Jones et al. 1999. PubMed ID: 10205261) or demonstrated to alter splicing via RNA analysis (Table S1, Wai et al. 2020. PubMed ID: 32123317). The c.4493G>C (p.Ser1498Thr) variant is interpreted as likely pathogenic. - |
Tuberous sclerosis syndrome Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at