chr5-128345468-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2
The NM_001999.4(FBN2):c.3106G>A(p.Glu1036Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E1036G) 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.3106G>A | p.Glu1036Lys | missense_variant | 24/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.2953G>A | p.Glu985Lys | missense_variant | 23/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.3106G>A | p.Glu1036Lys | missense_variant | 24/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000508989.5 | c.3007G>A | p.Glu1003Lys | missense_variant | 23/33 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251398Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135896
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727228
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 23, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 04, 2018 | The E1036K variant of uncertain significance in the FBN2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). E1036K 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, The E1036K variant does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with congenital contractural arachnodactyly (Collod-Beroud et al., 2003; Frédéric et al., 2009).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. - |
Congenital contractural arachnodactyly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at