chr5-128527932-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001999.4(FBN2):​c.472A>T​(p.Thr158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.96
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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=0.08681166).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FBN2NM_001999.4 linkuse as main transcriptc.472A>T p.Thr158Ser missense_variant 4/65 ENST00000262464.9
FBN2XM_017009228.3 linkuse as main transcriptc.472A>T p.Thr158Ser missense_variant 4/64

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FBN2ENST00000262464.9 linkuse as main transcriptc.472A>T p.Thr158Ser missense_variant 4/651 NM_001999.4 P1P35556-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152092
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460492
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726572
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152092
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74286
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 10, 2023This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 158 of the FBN2 protein (p.Thr158Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN2 protein function. ClinVar contains an entry for this variant (Variation ID: 350793). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is not present in population databases (gnomAD no frequency). -
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 provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 10, 2022Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18767143, 19006240) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.089
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
14
DANN
Benign
0.92
DEOGEN2
Benign
0.19
T;.;T;T;.
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.68
T;.;.;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.087
T;T;T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
0.35
N;.;N;.;.
MutationTaster
Benign
0.70
D;D;D;D
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.3
N;.;N;N;N
REVEL
Benign
0.11
Sift
Benign
0.63
T;.;T;T;T
Sift4G
Benign
1.0
.;.;.;T;T
Polyphen
0.0040
B;.;B;B;B
Vest4
0.23
MutPred
0.29
Gain of glycosylation at T158 (P = 0.2479);Gain of glycosylation at T158 (P = 0.2479);Gain of glycosylation at T158 (P = 0.2479);.;Gain of glycosylation at T158 (P = 0.2479);
MVP
0.46
MPC
0.34
ClinPred
0.11
T
GERP RS
2.9
Varity_R
0.039
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs886059904; hg19: chr5-127863625; API