chr16-2076569-A-G
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6
The NM_000548.5(TSC2):āc.2821A>Gā(p.Asn941Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,968 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N941T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
Publications
- tuberous sclerosisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- tuberous sclerosis 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
- lymphangioleiomyomatosisInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- tuberous sclerosis complexInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151854Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00 AC: 0AN: 250578 AF XY: 0.00
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461114Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726840 show subpopulations
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151854Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74132 show subpopulations ā ļø The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
ClinVar
Submissions by phenotype
not specified Uncertain:2
The N941D variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.It was not observed in approximately 6,500 individuals of European and African American ancestry inthe NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The N941D variant is a semi-conservative amino acid substitution, which may impactsecondary protein structure as these residues differ in some properties. This substitution occurs at aposition that is conserved across species. However, in silico analysis is inconsistent in its predictions asto whether or not the variant is damaging to the protein structure/function. Therefore, based on thecurrently available information, it is unclear whether this variant is a pathogenic variant or a rarebenign variant. -
Variant summary: TSC2 c.2821A>G (p.Asn941Asp) results in a conservative amino acid change located in the Tuberin, N-terminal domain (IPR024584) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.2821A>G 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: 238000). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Tuberous sclerosis 2 Benign:2
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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