rs766034866
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001999.4(FBN2):āc.5426T>Cā(p.Ile1809Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,482 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1809M) has been classified as Uncertain significance.
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.5426T>C | p.Ile1809Thr | missense_variant | 43/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.5273T>C | p.Ile1758Thr | missense_variant | 42/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.5426T>C | p.Ile1809Thr | missense_variant | 43/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000703783.1 | n.2210T>C | non_coding_transcript_exon_variant | 18/38 | |||||
FBN2 | ENST00000703785.1 | n.2129T>C | non_coding_transcript_exon_variant | 17/27 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461308Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727006
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 26, 2017 | p.Ile1809Thr (I1809T) ATT>ACT: c.5426 T>C in exon 43 of the FBN2 gene (NM_001999.3) The I1809T variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The I1809T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. Furthermore, the I1809T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported, indicating this region of the protein maybe tolerant of change. This variant was found in TAAD,FBN2 - |
Congenital contractural arachnodactyly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2017 | This sequence change replaces isoleucine with threonine at codon 1809 of the FBN2 protein (p.Ile1809Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs766034866, ExAC 0.006%). This variant has not been reported in the literature in individuals with a FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 213339). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on FBN2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at