rs774506901
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000548.5(TSC2):c.199G>A(p.Val67Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. V67V) has been classified as Benign.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251106Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135868
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461732Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727152
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Tuberous sclerosis syndrome Uncertain:1
This missense variant replaces valine with isoleucine at codon 67 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with autism spectrum disorder in the literature (PMID: 30763456). This variant has been identified in 2/251106 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
TSC2: PM2, BP4 -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.V67I variant (also known as c.199G>A), located in coding exon 2 of the TSC2 gene, results from a G to A substitution at nucleotide position 199. The valine at codon 67 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Tuberous sclerosis 2 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at