chr5-128369269-C-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2PP3_ModerateBP6BS2
The NM_001999.4(FBN2):āc.2161G>Cā(p.Gly721Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,908 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. G721S) has been classified as Likely benign.
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.2161G>C | p.Gly721Arg | missense_variant | 16/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.2008G>C | p.Gly670Arg | missense_variant | 15/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.2161G>C | p.Gly721Arg | missense_variant | 16/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000508989.5 | c.2062G>C | p.Gly688Arg | missense_variant | 15/33 | 2 | |||
FBN2 | ENST00000511489.1 | n.382G>C | non_coding_transcript_exon_variant | 4/6 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251282Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135788
GnomAD4 exome AF: 0.0000711 AC: 104AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59AN XY: 727212
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74272
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 24, 2016 | The p.G721R variant (also known as c.2161G>C), located in coding exon 16 of the FBN2 gene, results from a G to C substitution at nucleotide position 2161. The glycine at codon 721 is replaced by arginine, an amino acid with dissimilar properties. This variant was previously reported in the SNPDatabase as rs149733159. Based on data from ExAC, the C allele has an overall frequency of approximately <0.01% (3/121240). This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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 | Jul 21, 2022 | Has not been previously published as pathogenic or benign to our knowledge; Not located within exons 24-33, where the majority of pathogenic variants reported to date occur (Callewaert et al., 2009, Frederic et al., 2009); Does not occur within a calcium-binding-EGF-like domain (Callewaert et al., 2009, Frederic et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19006240, 18767143) - |
Congenital contractural arachnodactyly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at