rs141707850
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2
The NM_001999.4(FBN2):āc.6334A>Gā(p.Lys2112Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,614,070 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 32)
Exomes š: 0.00021 ( 0 hom. )
Consequence
FBN2
NM_001999.4 missense
NM_001999.4 missense
Scores
3
5
10
Clinical Significance
Conservation
PhyloP100: 2.77
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 Benign. Variant got -9 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, FBN2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.33632803).
BP6
?
Variant 5-128290843-T-C is Benign according to our data. Variant chr5-128290843-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213419.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000205 (300/1461784) while in subpopulation NFE AF= 0.000239 (266/1111928). AF 95% confidence interval is 0.000215. There are 0 homozygotes in gnomad4_exome. There are 137 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 18 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.6334A>G | p.Lys2112Glu | missense_variant | 50/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.6181A>G | p.Lys2061Glu | missense_variant | 49/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.6334A>G | p.Lys2112Glu | missense_variant | 50/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000703783.1 | n.3118A>G | non_coding_transcript_exon_variant | 25/38 | |||||
FBN2 | ENST00000703785.1 | n.3037A>G | non_coding_transcript_exon_variant | 24/27 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000143 AC: 36AN: 251214Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135762
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GnomAD4 exome AF: 0.000205 AC: 300AN: 1461784Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 137AN XY: 727204
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74466
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2024 | The p.K2112E variant (also known as c.6334A>G), located in coding exon 50 of the FBN2 gene, results from an A to G substitution at nucleotide position 6334. The lysine at codon 2112 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2023 | Has not been previously published as pathogenic or benign to our knowledge; Does not occur within a calcium-binding-EGF-like domain (Callewaert et al., 2009, Frederic et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function - |
Congenital contractural arachnodactyly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;.;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N
REVEL
Pathogenic
Sift
Benign
T;.;T
Polyphen
P;.;P
Vest4
MVP
MPC
0.96
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at