16-2064405-G-C
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000548.5(TSC2):āc.1577G>Cā(p.Ser526Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,588 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S526S) has been classified as Benign.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 152254Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 251166Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135810
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461334Hom.: 1 Cov.: 30 AF XY: 0.0000536 AC XY: 39AN XY: 726954
GnomAD4 genome AF: 0.000197 AC: 30AN: 152254Hom.: 1 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74386
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
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not specified Benign:2
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Variant summary: TSC2 c.1577G>C (p.Ser526Thr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251166 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05). To our knowledge, no occurrence of c.1577G>C in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 207659). Based on the evidence outlined above, the variant was classified as likely benign. -
Tuberous sclerosis 2 Benign:2
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Hereditary cancer-predisposing syndrome Benign:2
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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Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Uncertain:1
TSC2 NM_000548 exon 15 p.Ser526Thr (c.1577G>C): This variant has not been reported in the literature but is present in 15/126622 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs376573446). This variant is present in ClinVar (Variation ID:207659). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at