NM_001999.4:c.8444A>C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_001999.4(FBN2):āc.8444A>Cā(p.Lys2815Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,780 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
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151940Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251136Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135712
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727218
GnomAD4 genome AF: 0.0000329 AC: 5AN: 151940Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74206
ClinVar
Submissions by phenotype
not provided Uncertain:2
The FBN2 c.8444A>C; p.Lys2815Thr variant (rs757028268), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 528397). This variant is found in the general population with an overall allele frequency of 0.002% (5/282524 alleles) in the Genome Aggregation Database. The lysine at codon 2815 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.506). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
FBN2-related disorder Uncertain:1
The FBN2 c.8444A>C variant is predicted to result in the amino acid substitution p.Lys2815Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.K2815T variant (also known as c.8444A>C), located in coding exon 65 of the FBN2 gene, results from an A to C substitution at nucleotide position 8444. The lysine at codon 2815 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset Uncertain:1
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not specified Benign:1
Variant summary: FBN2 c.8444A>C (p.Lys2815Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 1613780 control chromosomes. The observed variant frequency is approximately 36.68 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN2 causing Aortopathy phenotype (1.3e-06). c.8444A>C has been reported in the literature in an individual affected with Spontaneous Coronary Artery Dissection, without strong evidence for causality (Tarr_2022). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35583931). ClinVar contains an entry for this variant (Variation ID: 528397). Based on the evidence outlined above, the variant was classified as likely benign. -
Congenital contractural arachnodactyly Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at