rs140276399
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The ENST00000262464.9(FBN2):c.5495G>A(p.Arg1832His) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,613,744 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. R1832C) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000262464.9 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.5495G>A | p.Arg1832His | missense_variant | 43/65 | ENST00000262464.9 | NP_001990.2 | |
FBN2 | XM_017009228.3 | c.5342G>A | p.Arg1781His | missense_variant | 42/64 | XP_016864717.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.5495G>A | p.Arg1832His | missense_variant | 43/65 | 1 | NM_001999.4 | ENSP00000262464 | P1 | |
FBN2 | ENST00000703783.1 | n.2279G>A | non_coding_transcript_exon_variant | 18/38 | ||||||
FBN2 | ENST00000703785.1 | n.2198G>A | non_coding_transcript_exon_variant | 17/27 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251270Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135780
GnomAD4 exome AF: 0.000111 AC: 162AN: 1461598Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 78AN XY: 727124
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 21, 2023 | Has not been previously published as pathogenic or benign to our knowledge; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2019 | - - |
Congenital contractural arachnodactyly Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | - - |
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 25, 2024 | - - |
FBN2-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 11, 2024 | The FBN2 c.5495G>A variant is predicted to result in the amino acid substitution p.Arg1832His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2023 | The p.R1832H variant (also known as c.5495G>A), located in coding exon 43 of the FBN2 gene, results from a G to A substitution at nucleotide position 5495. The arginine at codon 1832 is replaced by histidine, an amino acid with highly 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Connective tissue disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at