rs1060503506
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001999.4(FBN2):āc.425G>Cā(p.Gly142Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.9e-7 ( 0 hom. )
Consequence
FBN2
NM_001999.4 missense
NM_001999.4 missense
Scores
12
6
Clinical Significance
Conservation
PhyloP100: 3.93
Genes affected
FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, FBN2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.39408803).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.425G>C | p.Gly142Ala | missense_variant | 3/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.425G>C | p.Gly142Ala | missense_variant | 3/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.425G>C | p.Gly142Ala | missense_variant | 3/65 | 1 | NM_001999.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457524Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 725414
GnomAD4 exome
AF:
AC:
1
AN:
1457524
Hom.:
Cov.:
29
AF XY:
AC XY:
0
AN XY:
725414
Gnomad4 AFR exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2020 | The p.G142A variant (also known as c.425G>C), located in coding exon 3 of the FBN2 gene, results from a G to C substitution at nucleotide position 425. The glycine at codon 142 is replaced by alanine, an amino acid with similar properties, and is located in the EGF-like #02 domain. This amino acid position is well conserved in available vertebrate species; however, alanine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Congenital contractural arachnodactyly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2021 | This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 142 of the FBN2 protein (p.Gly142Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. 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: "Benign"; Align-GVGD: "Class C0"). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D
REVEL
Uncertain
Sift
Benign
T;.;T;D
Polyphen
P;.;P;D
Vest4
MutPred
Gain of catalytic residue at G142 (P = 0.1172);Gain of catalytic residue at G142 (P = 0.1172);Gain of catalytic residue at G142 (P = 0.1172);Gain of catalytic residue at G142 (P = 0.1172);
MVP
MPC
0.25
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at