rs143565958
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_001999.4(FBN2):c.2684A>G(p.Lys895Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,614,202 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 0 hom. )
Consequence
FBN2
NM_001999.4 missense
NM_001999.4 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 7.97
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 -19 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, FBN2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.016924411).
BP6
?
Variant 5-128350996-T-C is Benign according to our data. Variant chr5-128350996-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 519805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000696 (106/152328) while in subpopulation AFR AF= 0.00248 (103/41580). AF 95% confidence interval is 0.00209. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High AC in GnomAd at 106 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.2684A>G | p.Lys895Arg | missense_variant | 21/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.2531A>G | p.Lys844Arg | missense_variant | 20/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.2684A>G | p.Lys895Arg | missense_variant | 21/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000508989.5 | c.2585A>G | p.Lys862Arg | missense_variant | 20/33 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000696 AC: 106AN: 152210Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000199 AC: 50AN: 251356Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135866
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GnomAD4 exome AF: 0.0000732 AC: 107AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50AN XY: 727242
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GnomAD4 genome ? AF: 0.000696 AC: 106AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000671 AC XY: 50AN XY: 74492
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ClinVar
Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
FBN2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 06, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 26, 2017 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2021 | - - |
Congenital contractural arachnodactyly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;N
REVEL
Uncertain
Sift
Benign
T;.;T;T
Polyphen
B;.;B;B
Vest4
MVP
MPC
0.20
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