rs772617064
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2
The NM_000548.5(TSC2):c.152A>C(p.Glu51Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,764 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251096Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135874
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461696Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727148
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74282
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Uncertain:1Benign:2
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A TSC2 c.152A>C (p.Glu51Ala) variant is observed at fraction consistent with heterozygosity in the germline. This variant has been reported as germline variant in one female Dutch child affected with renal angiomyolipoma (Postema FAM et al.,PMID: 33686467). This variant is listed in the ClinVar database with conflicting interpretations of pathogenicity (uncertain significance by two submitters and likely benign by three submitters, ClinVar ID 1961840). TSC2 c.152A>C (p.Glu51Ala) is only observed on 2/152068 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on TSC2 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), TSC2 c.152A>C (p.Glu51Ala) is classified as being of uncertain clinical significance at this time. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
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Tuberous sclerosis syndrome Uncertain:1
This missense variant replaces glutamic acid with alanine at codon 51 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 4/251096 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. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an child with renal angiomyolipoma (PMID: 33686467); This variant is associated with the following publications: (PMID: 18466115, 33686467) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at