chr5-128350963-C-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_001999.4(FBN2):c.2717G>A(p.Arg906His) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,614,022 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. R906C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.2717G>A | p.Arg906His | missense_variant | 21/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.2564G>A | p.Arg855His | missense_variant | 20/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.2717G>A | p.Arg906His | missense_variant | 21/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000508989.5 | c.2618G>A | p.Arg873His | missense_variant | 20/33 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251404Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135882
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461882Hom.: 1 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 727246
GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74306
ClinVar
Submissions by phenotype
Congenital contractural arachnodactyly Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 07, 2022 | The p.R906H variant (also known as c.2717G>A), located in coding exon 21 of the FBN2 gene, results from a G to A substitution at nucleotide position 2717. The arginine at codon 906 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in two individuals from a thoracic aortic aneurysm and dissection (TAAD) cohort; however, clinical details were limited (Overwater E et al. Hum Mutat, 2018 09;39:1173-1192). This amino acid position is highly 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 2023 | Reported in two Dutch individuals with aortic aneurysm and/or dissection (Overwater et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not occur within a calcium-binding-EGF-like domain (Callewaert et al., 2009, Frederic et al., 2009); This variant is associated with the following publications: (PMID: 29907982) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at