5-128361741-C-T
Variant summary
Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_001999.4(FBN2):c.2536G>A(p.Glu846Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00021 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E846E) has been classified as Likely benign.
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
Publications
- congenital contractural arachnodactylyInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
- carpal tunnel syndromeInheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
- familial thoracic aortic aneurysm and aortic dissectionInheritance: AD Classification: LIMITED Submitted by: ClinGen
- macular degeneration, early-onsetInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Benign. The variant received -11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.2536G>A | p.Glu846Lys | missense_variant | Exon 19 of 65 | 1 | NM_001999.4 | ENSP00000262464.4 | ||
FBN2 | ENST00000508989.5 | c.2437G>A | p.Glu813Lys | missense_variant | Exon 18 of 33 | 2 | ENSP00000425596.1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152220Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000135 AC: 34AN: 251432 AF XY: 0.000118 show subpopulations
GnomAD4 exome AF: 0.000216 AC: 316AN: 1461830Hom.: 0 Cov.: 32 AF XY: 0.000199 AC XY: 145AN XY: 727222 show subpopulations
GnomAD4 genome AF: 0.000151 AC: 23AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74374 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
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Identified in a patient with features of Marfan syndrome who was incidentally diagnosed with subclinical tuberous sclerosis complex when a maternally inherited TSC1 variant was identified through whole exome sequencing (PMID: 29926239); Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (PMID: 19006240, 18767143); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19006240, 18767143, 29926239) -
Congenital contractural arachnodactyly Benign:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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not specified Uncertain:1
Variant summary: FBN2 c.2536G>A (p.Glu846Lys) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00014 in 251432 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FBN2 causing Nonsyndromic Heritable Thoracic Aortic Aneurysms And Dissections, allowing no conclusion about variant significance. c.2536G>A has been observed in an individual in whom there was suspicion of a connective tissue disorder; however this variant was not thought to be responsible for their clinical phenotype (example: Caylor_2018). The variant was also identified in at least 1 individual clinically diagnosed with classical Ehlers-Danlos syndrome (example: Vandersteen_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Nonsyndromic Heritable Thoracic Aortic Aneurysms And Dissections. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29926239, 37813462). ClinVar contains an entry for this variant (Variation ID: 213392). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.E846K variant (also known as c.2536G>A), located in coding exon 19 of the FBN2 gene, results from a G to A substitution at nucleotide position 2536. The glutamic acid at codon 846 is replaced by lysine, an amino acid with similar properties. This alteration was reported in a patient with suspicion of Marfan syndrome (Caylor RC et al. Neurogenetics, 2018 Aug;19(3):205-213). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset Uncertain:1
FBN2 NM_001999.3 exon 19 p.Glu846Lys (c.2536G>A): This variant has not been reported in the literature but is present in 0.02% (37/129150) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-127697434-C-T). This variant is present in ClinVar (Variation ID:213392). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at