16-2079289-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_StrongBP6BS2
The NM_000548.5(TSC2):c.3145G>A(p.Glu1049Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,844 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 -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152140Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1460704Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726644
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74316
ClinVar
Submissions by phenotype
not provided Uncertain:4
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with cardiac rhabdomyoma; however, no other features of TSC were noted in the patient (PMID: 19254590); This variant is associated with the following publications: (PMID: 22558107, 34426522, 37800821, 19254590, 30476936) -
The TSC2 c.3145G>A; p.Glu1049Lys variant (rs796053492) is reported in the literature in a fetus with prenatal tuberous sclerosis features (Milunsky 2009). This variant is also reported in ClinVar (Variation ID: 207741), but is only observed on one allele in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.931). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Milunsky A et al. Prenatal molecular diagnosis of tuberous sclerosis complex. Am J Obstet Gynecol. 2009 Mar;200(3):321.e1-6. PMID: 19254590. -
Tuberous sclerosis 2 Uncertain:1Benign:1
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not specified Uncertain:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Absent from ExAC. Detected in control and affected groups in autism study. Also published in study of pregnant women at risk for having child with TSC. No other pubs found. -
Tuberous sclerosis syndrome Uncertain:1
This missense variant replaces glutamic acid with lysine at codon 1049 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an infant with a diagnosis of cardiac rhabdomyoma via fetal ultrasound and confirmed at birth that underwent prenatal genetic testing for tuberous sclerosis complex (PMID: 19254590). The infant had no other features of tuberous sclerosis complex and there was no known family history. This variant has been identified in 1/31354 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. -
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Uncertain:1
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TSC2-related disorder Uncertain:1
The TSC2 c.3145G>A variant is predicted to result in the amino acid substitution p.Glu1049Lys. This variant was reported in an individual with suspected tuberous sclerosis; however, pathogenicity was not established (Milunsky et al 2009. PubMed ID: 19254590). This variant is reported in 0.0065% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Isolated focal cortical dysplasia type II Uncertain:1
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Hereditary cancer-predisposing syndrome Benign: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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at