rs576123258
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_001999.4(FBN2):āc.1238A>Gā(p.Tyr413Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,846 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 ). Synonymous variant affecting the same amino acid position (i.e. Y413Y) has been classified as Likely benign.
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.1238A>G | p.Tyr413Cys | missense_variant | 10/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.1085A>G | p.Tyr362Cys | missense_variant | 9/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.1238A>G | p.Tyr413Cys | missense_variant | 10/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000508989.5 | c.1139A>G | p.Tyr380Cys | missense_variant | 9/33 | 2 | |||
FBN2 | ENST00000703787.1 | n.945A>G | non_coding_transcript_exon_variant | 9/10 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152238Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000479 AC: 12AN: 250300Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135334
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461608Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42AN XY: 727118
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74376
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2019 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Although it introduces a cysteine residue, it does not occur within a calcium-binding EGF-like domain of the FBN2 gene; Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2 related disorders (Frederic et al., 2009); Reported as a variant of uncertain significance in ClinVar (SCV000553186.2; Landrum et al., 2016) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | - - |
Congenital contractural arachnodactyly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 15, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 413 of the FBN2 protein (p.Tyr413Cys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN2 protein function. ClinVar contains an entry for this variant (Variation ID: 411820). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is present in population databases (rs576123258, gnomAD 0.01%). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at