5-128395262-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_001999.4(FBN2):​c.1091G>A​(p.Gly364Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,966 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. G364A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

7
9
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.33
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 -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.849
BP6
Variant 5-128395262-C-T is Benign according to our data. Variant chr5-128395262-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458729.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN2NM_001999.4 linkc.1091G>A p.Gly364Asp missense_variant Exon 9 of 65 ENST00000262464.9 NP_001990.2 P35556-1
FBN2XM_017009228.3 linkc.1079-1894G>A intron_variant Intron 8 of 63 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkc.1091G>A p.Gly364Asp missense_variant Exon 9 of 65 1 NM_001999.4 ENSP00000262464.4 P35556-1
FBN2ENST00000508989.5 linkc.992G>A p.Gly331Asp missense_variant Exon 8 of 33 2 ENSP00000425596.1 D6RJI3
FBN2ENST00000703787.1 linkn.798G>A non_coding_transcript_exon_variant Exon 8 of 10

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152146
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:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
250950
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135612
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000529
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000369
AC:
54
AN:
1461820
Hom.:
0
Cov.:
32
AF XY:
0.0000344
AC XY:
25
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000459
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74310
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:
0.0000441
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000283
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Dec 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.G364D variant (also known as c.1091G>A), located in coding exon 9 of the FBN2 gene, results from a G to A substitution at nucleotide position 1091. The glycine at codon 364 is replaced by aspartic acid, an amino acid with 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided Uncertain:1
Oct 19, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Frederic et al., 2009).; This variant is associated with the following publications: (PMID: 18767143) -

Congenital contractural arachnodactyly Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.41
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
D;.;D;T
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;.;.;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.85
D;D;D;D
MetaSVM
Uncertain
0.62
D
MutationAssessor
Uncertain
2.2
M;.;M;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-5.8
D;.;D;D
REVEL
Pathogenic
0.81
Sift
Benign
0.032
D;.;D;D
Sift4G
Benign
0.14
.;.;.;T
Polyphen
0.94
P;.;P;D
Vest4
0.83
MutPred
0.66
Loss of catalytic residue at C366 (P = 0.1481);.;Loss of catalytic residue at C366 (P = 0.1481);.;
MVP
0.95
MPC
0.70
ClinPred
0.66
D
GERP RS
4.4
Varity_R
0.50
gMVP
0.79

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: rs762615993; hg19: chr5-127730955; API