rs764529584
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000548.5(TSC2):c.344G>A(p.Arg115His) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. R115C) has been classified as Likely benign.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.344G>A | p.Arg115His | missense_variant | 5/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.344G>A | p.Arg115His | missense_variant | 5/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000596 AC: 15AN: 251472Hom.: 0 AF XY: 0.0000956 AC XY: 13AN XY: 135916
GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461872Hom.: 1 Cov.: 31 AF XY: 0.0000646 AC XY: 47AN XY: 727238
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 11, 2021 | - - |
Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 16, 2023 | This missense variant replaces arginine with histidine at codon 115 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 tuberous sclerosis complex in the literature. This variant has been identified in 16/282852 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at