rs563921589
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2BP4_ModerateBP6_Very_StrongBS1BS2
The NM_001999.4(FBN2):c.3203G>A(p.Arg1068Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 1 hom. )
Consequence
FBN2
NM_001999.4 missense
NM_001999.4 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 3.40
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 -17 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.
BP4
Computational evidence support a benign effect (MetaRNN=0.13782609).
BP6
Variant 5-128345371-C-T is Benign according to our data. Variant chr5-128345371-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 528436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000788 (12/152228) while in subpopulation SAS AF= 0.00249 (12/4818). AF 95% confidence interval is 0.00144. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.3203G>A | p.Arg1068Gln | missense_variant | 24/65 | ENST00000262464.9 | NP_001990.2 | |
FBN2 | XM_017009228.3 | c.3050G>A | p.Arg1017Gln | missense_variant | 23/64 | XP_016864717.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.3203G>A | p.Arg1068Gln | missense_variant | 24/65 | 1 | NM_001999.4 | ENSP00000262464.4 | ||
FBN2 | ENST00000508989.5 | c.3104G>A | p.Arg1035Gln | missense_variant | 23/33 | 2 | ENSP00000425596.1 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152110Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000155 AC: 39AN: 251186Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135788
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GnomAD4 exome AF: 0.000101 AC: 147AN: 1461816Hom.: 1 Cov.: 32 AF XY: 0.000142 AC XY: 103AN XY: 727216
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GnomAD4 genome AF: 0.0000788 AC: 12AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74438
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2020 | - - |
Congenital contractural arachnodactyly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 27, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;.;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;N
REVEL
Uncertain
Sift
Uncertain
D;.;D;D
Sift4G
Benign
.;.;.;T
Polyphen
D;.;D;P
Vest4
MutPred
Gain of methylation at K1072 (P = 0.0579);.;Gain of methylation at K1072 (P = 0.0579);.;
MVP
MPC
0.59
ClinPred
T
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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