5-128361741-C-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001999.4(FBN2):​c.2536G>A​(p.Glu846Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00021 in 1,614,050 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). Synonymous variant affecting the same amino acid position (i.e. E846E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

1
8
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 4.99

Publications

1 publications found
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]
FBN2 Gene-Disease associations (from GenCC):
  • congenital contractural arachnodactyly
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
  • carpal tunnel syndrome
    Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
  • familial thoracic aortic aneurysm and aortic dissection
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • macular degeneration, early-onset
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.26250064).
BP6
Variant 5-128361741-C-T is Benign according to our data. Variant chr5-128361741-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213392.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000151 (23/152220) while in subpopulation NFE AF = 0.000309 (21/68032). AF 95% confidence interval is 0.000207. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN2NM_001999.4 linkc.2536G>A p.Glu846Lys missense_variant Exon 19 of 65 ENST00000262464.9 NP_001990.2 P35556-1
FBN2XM_017009228.3 linkc.2383G>A p.Glu795Lys missense_variant Exon 18 of 64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkc.2536G>A p.Glu846Lys missense_variant Exon 19 of 65 1 NM_001999.4 ENSP00000262464.4 P35556-1
FBN2ENST00000508989.5 linkc.2437G>A p.Glu813Lys missense_variant Exon 18 of 33 2 ENSP00000425596.1 D6RJI3

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.000309
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000135
AC:
34
AN:
251432
AF XY:
0.000118
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000299
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000216
AC:
316
AN:
1461830
Hom.:
0
Cov.:
32
AF XY:
0.000199
AC XY:
145
AN XY:
727222
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.000279
AC:
310
AN:
1111974
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.456
Heterozygous variant carriers
0
19
38
58
77
96
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152220
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74374
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41466
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000309
AC:
21
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000296
Hom.:
0
Bravo
AF:
0.000170
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000148
AC:
18
EpiCase
AF:
0.000218
EpiControl
AF:
0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
May 29, 2020
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 21, 2025
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Identified in a patient with features of Marfan syndrome who was incidentally diagnosed with subclinical tuberous sclerosis complex when a maternally inherited TSC1 variant was identified through whole exome sequencing (PMID: 29926239); Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (PMID: 19006240, 18767143); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19006240, 18767143, 29926239) -

Congenital contractural arachnodactyly Benign:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Jun 23, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: FBN2 c.2536G>A (p.Glu846Lys) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00014 in 251432 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FBN2 causing Nonsyndromic Heritable Thoracic Aortic Aneurysms And Dissections, allowing no conclusion about variant significance. c.2536G>A has been observed in an individual in whom there was suspicion of a connective tissue disorder; however this variant was not thought to be responsible for their clinical phenotype (example: Caylor_2018). The variant was also identified in at least 1 individual clinically diagnosed with classical Ehlers-Danlos syndrome (example: Vandersteen_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Nonsyndromic Heritable Thoracic Aortic Aneurysms And Dissections. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29926239, 37813462). ClinVar contains an entry for this variant (Variation ID: 213392). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Mar 18, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.E846K variant (also known as c.2536G>A), located in coding exon 19 of the FBN2 gene, results from a G to A substitution at nucleotide position 2536. The glutamic acid at codon 846 is replaced by lysine, an amino acid with similar properties. This alteration was reported in a patient with suspicion of Marfan syndrome (Caylor RC et al. Neurogenetics, 2018 Aug;19(3):205-213). 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
-
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

FBN2 NM_001999.3 exon 19 p.Glu846Lys (c.2536G>A): This variant has not been reported in the literature but is present in 0.02% (37/129150) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-127697434-C-T). This variant is present in ClinVar (Variation ID:213392). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.13
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
T;.;T;D
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.86
D;.;.;D
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.26
T;T;T;T
MetaSVM
Uncertain
-0.098
T
MutationAssessor
Benign
0.57
N;.;N;.
PhyloP100
5.0
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-2.1
N;.;N;N
REVEL
Uncertain
0.40
Sift
Benign
0.090
T;.;T;T
Sift4G
Benign
0.19
.;.;.;T
Polyphen
0.65
P;.;P;P
Vest4
0.43
MVP
0.32
MPC
0.53
ClinPred
0.29
T
GERP RS
4.8
Varity_R
0.19
gMVP
0.67
Mutation Taster
=50/50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs375666281; hg19: chr5-127697434; API