rs140276399

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The ENST00000262464.9(FBN2):​c.5495G>A​(p.Arg1832His) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1832C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

FBN2
ENST00000262464.9 missense

Scores

4
10
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 6.16
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.829
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBN2NM_001999.4 linkuse as main transcriptc.5495G>A p.Arg1832His missense_variant 43/65 ENST00000262464.9 NP_001990.2
FBN2XM_017009228.3 linkuse as main transcriptc.5342G>A p.Arg1781His missense_variant 42/64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkuse as main transcriptc.5495G>A p.Arg1832His missense_variant 43/651 NM_001999.4 ENSP00000262464 P1P35556-1
FBN2ENST00000703783.1 linkuse as main transcriptn.2279G>A non_coding_transcript_exon_variant 18/38
FBN2ENST00000703785.1 linkuse as main transcriptn.2198G>A non_coding_transcript_exon_variant 17/27

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251270
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135780
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000111
AC:
162
AN:
1461598
Hom.:
0
Cov.:
31
AF XY:
0.000107
AC XY:
78
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000123
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 21, 2023Has not been previously published as pathogenic or benign to our knowledge; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (Callewaert et al., 2009; Frederic et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19006240, 18767143) -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2019- -
Congenital contractural arachnodactyly Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 25, 2024- -
FBN2-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 11, 2024The FBN2 c.5495G>A variant is predicted to result in the amino acid substitution p.Arg1832His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0098% of alleles in individuals of South Asian 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 30, 2023The p.R1832H variant (also known as c.5495G>A), located in coding exon 43 of the FBN2 gene, results from a G to A substitution at nucleotide position 5495. The arginine at codon 1832 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Connective tissue disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.66
D;.;D
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.90
D;.;.
M_CAP
Benign
0.055
D
MetaRNN
Pathogenic
0.83
D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Benign
1.1
L;.;L
MutationTaster
Benign
0.96
D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-2.9
D;.;D
REVEL
Pathogenic
0.66
Sift
Benign
0.083
T;.;T
Polyphen
0.59
P;.;P
Vest4
0.92
MVP
0.99
MPC
0.41
ClinPred
0.29
T
GERP RS
4.1
Varity_R
0.14
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140276399; hg19: chr5-127641568; COSMIC: COSV52521806; API