NM_001999.4:c.806T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_001999.4(FBN2):​c.806T>C​(p.Ile269Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,736 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 1 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

2
5
12

Clinical Significance

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

Conservation

PhyloP100: 4.30

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 -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.42067215).
BP6
Variant 5-128464744-A-G is Benign according to our data. Variant chr5-128464744-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411837.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000253 (37/1461396) while in subpopulation MID AF = 0.00108 (6/5556). AF 95% confidence interval is 0.00047. There are 1 homozygotes in GnomAdExome4. There are 29 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN2NM_001999.4 linkc.806T>C p.Ile269Thr missense_variant Exon 6 of 65 ENST00000262464.9 NP_001990.2 P35556-1
FBN2XM_017009228.3 linkc.806T>C p.Ile269Thr missense_variant Exon 6 of 64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkc.806T>C p.Ile269Thr missense_variant Exon 6 of 65 1 NM_001999.4 ENSP00000262464.4 P35556-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152222
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:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000319
AC:
8
AN:
250716
AF XY:
0.0000590
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1461396
Hom.:
1
Cov.:
32
AF XY:
0.0000399
AC XY:
29
AN XY:
727020
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33462
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.000302
AC:
26
AN:
86228
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53322
Middle Eastern (MID)
AF:
0.00108
AC:
6
AN:
5556
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111924
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60354
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
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
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152340
Hom.:
0
Cov.:
32
AF XY:
0.0000268
AC XY:
2
AN XY:
74496
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41582
American (AMR)
AF:
0.00
AC:
0
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
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:
0.0000843
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000494
AC:
6

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Nov 09, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Congenital contractural arachnodactyly Benign:1
Jul 07, 2023
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
0.73
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Uncertain
0.63
D;.;D;T;.
Eigen
Benign
-0.18
Eigen_PC
Benign
0.022
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.88
D;.;.;T;D
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.42
T;T;T;T;T
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
-0.31
N;.;N;.;.
PhyloP100
4.3
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-2.9
D;.;D;D;D
REVEL
Uncertain
0.31
Sift
Benign
0.27
T;.;T;T;T
Sift4G
Benign
0.076
.;.;.;T;T
Polyphen
0.0030
B;.;B;B;B
Vest4
0.88
MutPred
0.60
Loss of stability (P = 0.0055);.;Loss of stability (P = 0.0055);.;Loss of stability (P = 0.0055);
MVP
0.49
MPC
0.59
ClinPred
0.13
T
GERP RS
5.1
Varity_R
0.20
gMVP
0.37
Mutation Taster
=67/33
polymorphism

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

Other links and lift over

dbSNP: rs771008563; hg19: chr5-127800437; COSMIC: COSV52503368; API