5-128291568-G-C
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001999.4(FBN2):c.6253C>G(p.Pro2085Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.6253C>G | p.Pro2085Ala | missense_variant | Exon 49 of 65 | 1 | NM_001999.4 | ENSP00000262464.4 | ||
FBN2 | ENST00000703783.1 | n.3037C>G | non_coding_transcript_exon_variant | Exon 24 of 38 | ||||||
FBN2 | ENST00000703785.1 | n.2956C>G | non_coding_transcript_exon_variant | Exon 23 of 27 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152118Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000259 AC: 65AN: 251186Hom.: 0 AF XY: 0.000273 AC XY: 37AN XY: 135750
GnomAD4 exome AF: 0.000147 AC: 215AN: 1461726Hom.: 1 Cov.: 31 AF XY: 0.000166 AC XY: 121AN XY: 727170
GnomAD4 genome AF: 0.000190 AC: 29AN: 152236Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74420
ClinVar
Submissions by phenotype
not provided Benign:3
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Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2 related disorders (Collod-Beroud et al., 2003; Frederic et al., 2009); Reported in ClinVar (ClinVar Variant ID# 213344; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24833718) -
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Congenital contractural arachnodactyly Benign:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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not specified Benign:1
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FBN2-related disorder Benign:1
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
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at