chr5-128338114-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_001999.4(FBN2):c.3481G>A(p.Glu1161Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. E1161G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.3481G>A | p.Glu1161Lys | missense_variant | 27/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.3328G>A | p.Glu1110Lys | missense_variant | 26/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.3481G>A | p.Glu1161Lys | missense_variant | 27/65 | 1 | NM_001999.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461668Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727118
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2022 | Identified in a patient with tall stature, arachnodactyly, camptodactyly, scoliosis, pectus deformity, myopia, and beaked nose but it is unknown whether this individual was screened for variants in other genes associated with this phenotype (Callewaert et al., 2009); Identified in an individual with pes planus, pectus abnormality, facial features, elbow hyperextensibility, high myopia, mild aortic dilatation, severe lumbar scoliosis, wrist and thumb sign, high-arched palate, and marfanoid habitus who also harbored a variant in the FBN1 gene (Najafi et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (Callewaert et al., 2009; Frederic et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19006240, 18767143, 31506931) - |
Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | FBN2 NM_001999.3 exon27 p.Glu1161Lys (c.3481G>A): This variant has been reported in the literature in 1 individual with congenital contractural arachnodactyly, segregating with disease in 4 affected family members (Callewaert 2009 PMID:19006240). Additionally, this variant is not present in large control databases. This variant is present in ClinVar (Variation ID: 458759). Evolutionary consevation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Congenital contractural arachnodactyly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 expected to disrupt FBN2 protein function. ClinVar contains an entry for this variant (Variation ID: 458759). This missense change has been observed in individual(s) with autosomal dominant congenital contractural arachnodactyly (PMID: 19006240, 31506931). It has also been observed to segregate with disease in related individuals. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1161 of the FBN2 protein (p.Glu1161Lys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at