rs1057519321
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_001999.4(FBN2):c.2945G>T(p.Cys982Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C982Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.2945G>T | p.Cys982Phe | missense_variant | 23/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.2792G>T | p.Cys931Phe | missense_variant | 22/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.2945G>T | p.Cys982Phe | missense_variant | 23/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000508989.5 | c.2846G>T | p.Cys949Phe | missense_variant | 22/33 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Marfan syndrome;C0220668:Congenital contractural arachnodactyly Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS | Jan 01, 2016 | - - |
Congenital contractural arachnodactyly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2021 | This sequence change replaces cysteine with phenylalanine at codon 982 of the FBN2 protein (p.Cys982Phe). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of FBN2-related disease (PMID: 29501612). ClinVar contains an entry for this variant (Variation ID: 375300). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN2 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at