chr5-128349443-C-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_001999.4(FBN2):c.2893G>A(p.Val965Ile) variant causes a missense change. The variant allele was found at a frequency of 0.694 in 1,613,198 control chromosomes in the GnomAD database, including 390,972 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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 |
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FBN2 | ENST00000262464.9 | c.2893G>A | p.Val965Ile | missense_variant | Exon 23 of 65 | 1 | NM_001999.4 | ENSP00000262464.4 | ||
FBN2 | ENST00000508989.5 | c.2794G>A | p.Val932Ile | missense_variant | Exon 22 of 33 | 2 | ENSP00000425596.1 |
Frequencies
GnomAD3 genomes AF: 0.686 AC: 104185AN: 151884Hom.: 35967 Cov.: 32
GnomAD3 exomes AF: 0.728 AC: 182726AN: 250892Hom.: 67593 AF XY: 0.725 AC XY: 98239AN XY: 135580
GnomAD4 exome AF: 0.695 AC: 1015407AN: 1461196Hom.: 354976 Cov.: 44 AF XY: 0.696 AC XY: 505945AN XY: 726886
GnomAD4 genome AF: 0.686 AC: 104264AN: 152002Hom.: 35996 Cov.: 32 AF XY: 0.690 AC XY: 51239AN XY: 74286
ClinVar
Submissions by phenotype
Congenital contractural arachnodactyly Benign:6
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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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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not specified Benign:4
This is a RefSeq error. The reference base (c.2893G) is the minor allele. This a llele (G) has been identified in 32% (2754/8600) of European American chromosome s and 37% (1640/4406) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs154001) and thus meets c riteria to be classified as benign. -
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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not provided Benign:2
Variant summary: The FBN2 c.2893G>A (p.Val965Ile) variant causes a missense change involving the alteration of a conserved nucleotide that 4/4 in silico tools (Mutation Taster not captured here due to low p-value) predict a benign outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 0.7233944 (87496/120952 (32094 homozygotes)), therefore, suggesting that the A allele is the major allele, the allele most commonly observed in the general population. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
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Familial thoracic aortic aneurysm and aortic dissection Benign:1
This alteration is classified as 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. -
Ehlers-Danlos syndrome Benign:1
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Macular degeneration, early-onset Benign:1
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Connective tissue disorder Benign:1
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Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at