16-2086380-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_000548.5(TSC2):c.4849+1G>T variant causes a splice donor, intron 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 Pathogenic (★).
Frequency
Consequence
NM_000548.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 18, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1430667). Disruption of this splice site has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 17304050; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 37 of the TSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). - |
TSC2-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 29, 2023 | The TSC2 c.4849+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/1430667/). Variants that disrupt the consensus splice donor site in TSC2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.