5-128395262-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2
The NM_001999.4(FBN2):c.1091G>A(p.Gly364Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,966 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G364A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.1091G>A | p.Gly364Asp | missense_variant | Exon 9 of 65 | 1 | NM_001999.4 | ENSP00000262464.4 | ||
FBN2 | ENST00000508989.5 | c.992G>A | p.Gly331Asp | missense_variant | Exon 8 of 33 | 2 | ENSP00000425596.1 | |||
FBN2 | ENST00000703787.1 | n.798G>A | non_coding_transcript_exon_variant | Exon 8 of 10 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250950Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135612
GnomAD4 exome AF: 0.0000369 AC: 54AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727212
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74310
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.G364D variant (also known as c.1091G>A), located in coding exon 9 of the FBN2 gene, results from a G to A substitution at nucleotide position 1091. The glycine at codon 364 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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).; This variant is associated with the following publications: (PMID: 18767143) -
Congenital contractural arachnodactyly Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at