rs749819006
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_001999.4(FBN2):āc.257C>Gā(p.Pro86Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. P86S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001999.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.257C>G | p.Pro86Arg | missense_variant, splice_region_variant | 2/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.257C>G | p.Pro86Arg | missense_variant, splice_region_variant | 2/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.257C>G | p.Pro86Arg | missense_variant, splice_region_variant | 2/65 | 1 | NM_001999.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000322 AC: 8AN: 248816Hom.: 0 AF XY: 0.0000520 AC XY: 7AN XY: 134634
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461102Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 726816
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2019 | The p.P86R variant (also known as c.257C>G), located in coding exon 2 of the FBN2 gene, results from a C to G substitution at nucleotide position 257. The proline at codon 86 is replaced by arginine, an amino acid with dissimilar properties, and is located in the EGF-like #01 domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 02, 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; Does not affect a cysteine residue 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 in ClinVar as a variant of uncertain significance (ClinVar Variant ID 458744; Landrum et al., 2016) - |
Congenital contractural arachnodactyly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2023 | This variant is present in population databases (rs749819006, gnomAD 0.007%). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 458744). This missense change has been observed in individual(s) with clinical features of FBN2-related conditions (Invitae). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the FBN2 protein (p.Pro86Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at