5-128338975-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2
The NM_001999.4(FBN2):c.3430G>A(p.Glu1144Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E1144E) has been classified as Likely benign.
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.3430G>A | p.Glu1144Lys | missense_variant | 26/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.3277G>A | p.Glu1093Lys | missense_variant | 25/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.3430G>A | p.Glu1144Lys | missense_variant | 26/65 | 1 | NM_001999.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251380Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135852
GnomAD4 exome AF: 0.0000835 AC: 122AN: 1461784Hom.: 0 Cov.: 31 AF XY: 0.0000839 AC XY: 61AN XY: 727200
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Macular degeneration, early-onset Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2014 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2023 | The p.E1144K variant (also known as c.3430G>A), located in coding exon 26 of the FBN2 gene, results from a G to A substitution at nucleotide position 3430. The glutamic acid at codon 1144 is replaced by lysine, an amino acid with similar properties. This variant was reported to co-segregate with early onset macular dystrophy in five relatives in one family (Ratnapriya R et al. Hum Mol Genet. 2014;23(21):5827-3). This amino acid position is not 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 variant remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2023 | Identified in several members of one family with early onset macular degeneration (Ratnapriya et al., 2014); 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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31624054, 24899048, 25986072, 36971708, 37100863) - |
Congenital contractural arachnodactyly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1144 of the FBN2 protein (p.Glu1144Lys). This variant is present in population databases (rs200060005, gnomAD 0.006%). This missense change has been observed in individual(s) with early-onset macular dystrophy (PMID: 24899048). ClinVar contains an entry for this variant (Variation ID: 161445). 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 not expected to disrupt FBN2 protein function with a negative predictive value of 80%. 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. - |
Connective tissue disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Jun 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at