5-128278767-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4BP6_ModerateBS2

The NM_001999.4(FBN2):​c.7213G>A​(p.Val2405Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,613,980 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2405L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

5
5
8

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.96

Publications

2 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 -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.35018677).
BP6
Variant 5-128278767-C-T is Benign according to our data. Variant chr5-128278767-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 528416.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN2NM_001999.4 linkc.7213G>A p.Val2405Ile missense_variant Exon 57 of 65 ENST00000262464.9 NP_001990.2 P35556-1
FBN2XM_017009228.3 linkc.7060G>A p.Val2354Ile missense_variant Exon 56 of 64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkc.7213G>A p.Val2405Ile missense_variant Exon 57 of 65 1 NM_001999.4 ENSP00000262464.4 P35556-1
FBN2ENST00000703783.1 linkn.3997G>A non_coding_transcript_exon_variant Exon 32 of 38

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
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
GnomAD2 exomes
AF:
0.0000319
AC:
8
AN:
251048
AF XY:
0.0000369
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000301
AC:
44
AN:
1461832
Hom.:
0
Cov.:
31
AF XY:
0.0000330
AC XY:
24
AN XY:
727214
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39690
South Asian (SAS)
AF:
0.0000696
AC:
6
AN:
86256
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000261
AC:
29
AN:
1111972
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74320
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41426
American (AMR)
AF:
0.0000655
AC:
1
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.000192
AC:
1
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.0000612
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly Benign:1
May 15, 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
Benign
0.12
BayesDel_addAF
Benign
-0.050
T
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.42
T;.;T
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;.;.
M_CAP
Benign
0.046
D
MetaRNN
Benign
0.35
T;T;T
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Uncertain
2.1
M;.;M
PhyloP100
5.0
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.80
N;.;N
REVEL
Uncertain
0.56
Sift
Benign
0.031
D;.;D
Polyphen
1.0
D;.;D
Vest4
0.25
MutPred
0.60
Gain of methylation at K2407 (P = 0.1639);.;Gain of methylation at K2407 (P = 0.1639);
MVP
0.60
MPC
0.73
ClinPred
0.33
T
GERP RS
5.1
Varity_R
0.14
gMVP
0.38
Mutation Taster
=34/66
disease causing

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: rs753865904; hg19: chr5-127614459; API