rs139620380
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_001999.4(FBN2):āc.3062G>Cā(p.Arg1021Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,074 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1021H) 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.3062G>C | p.Arg1021Pro | missense_variant | 24/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.2909G>C | p.Arg970Pro | missense_variant | 23/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.3062G>C | p.Arg1021Pro | missense_variant | 24/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000508989.5 | c.2963G>C | p.Arg988Pro | missense_variant | 23/33 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251456Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135900
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
Congenital contractural arachnodactyly Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2022 | This variant has not been reported in the literature in individuals affected with FBN2-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 213298). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1021 of the FBN2 protein (p.Arg1021Pro). - |
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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2017 | p.Arg1021Pro (CGC>CCC): c.3062 G>C in exon 24 of the FBN2 gene (NM_001999.3) The R1021P variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The R1021P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1021P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is possibly damaging to protein structure/function. However, no missense mutations in nearby residues have been reported in association with congenital contractural arachnodactyly. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at