rs146807421
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_001999.4(FBN2):c.157G>A(p.Gly53Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,608,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. G53D) has been classified as Likely benign.
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.157G>A | p.Gly53Ser | missense_variant | 1/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.157G>A | p.Gly53Ser | missense_variant | 1/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.157G>A | p.Gly53Ser | missense_variant | 1/65 | 1 | NM_001999.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000382 AC: 9AN: 235404Hom.: 0 AF XY: 0.0000234 AC XY: 3AN XY: 128342
GnomAD4 exome AF: 0.0000234 AC: 34AN: 1455836Hom.: 0 Cov.: 32 AF XY: 0.0000262 AC XY: 19AN XY: 723952
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74482
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 07, 2015 | p.Gly53Ser (G53S) GGC>AGC: c.157 G>A in exon 1 of the FBN2 gene (NM_001999.3) The G53S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G53S variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, the G53S 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. Although a missense mutation in the same residue (G53D) has been reported in association with adolescent idiopathic scoliosis, other missense mutations in nearby residues have not been reported, indicating this region may be tolerant of change. Additionally, this substitution occurs at a position that is not conserved among species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. 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 TAADV2-PANCARD - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 24, 2023 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 06, 2021 | The p.G53S variant (also known as c.157G>A), located in coding exon 1 of the FBN2 gene, results from a G to A substitution at nucleotide position 157. The glycine at codon 53 is replaced by serine, an amino acid with similar properties. This amino acid position is well 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. - |
Ehlers-Danlos syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 10, 2022 | - - |
Congenital contractural arachnodactyly Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at