rs34450503

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001999.4(FBN2):​c.1592G>C​(p.Gly531Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000995 in 1,613,724 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G531G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00098 ( 9 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

1
12
6

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.55
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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009535283).
BP6
Variant 5-128392029-C-G is Benign according to our data. Variant chr5-128392029-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 213263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128392029-C-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00116 (177/152310) while in subpopulation SAS AF = 0.00207 (10/4830). AF 95% confidence interval is 0.00149. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
BS2
High AC in GnomAd4 at 177 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN2NM_001999.4 linkc.1592G>C p.Gly531Ala missense_variant Exon 11 of 65 ENST00000262464.9 NP_001990.2 P35556-1
FBN2XM_017009228.3 linkc.1439G>C p.Gly480Ala missense_variant Exon 10 of 64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkc.1592G>C p.Gly531Ala missense_variant Exon 11 of 65 1 NM_001999.4 ENSP00000262464.4 P35556-1
FBN2ENST00000508989.5 linkc.1493G>C p.Gly498Ala missense_variant Exon 10 of 33 2 ENSP00000425596.1 D6RJI3
FBN2ENST00000703787.1 linkn.1299G>C non_coding_transcript_exon_variant Exon 10 of 10

Frequencies

GnomAD3 genomes
AF:
0.00116
AC:
177
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00691
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.00207
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00175
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.00136
AC:
342
AN:
251046
AF XY:
0.00148
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00636
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00217
Gnomad NFE exome
AF:
0.00155
Gnomad OTH exome
AF:
0.000980
GnomAD4 exome
AF:
0.000978
AC:
1429
AN:
1461414
Hom.:
9
Cov.:
30
AF XY:
0.00106
AC XY:
771
AN XY:
727004
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33466
Gnomad4 AMR exome
AF:
0.000134
AC:
6
AN:
44722
Gnomad4 ASJ exome
AF:
0.00635
AC:
166
AN:
26124
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39626
Gnomad4 SAS exome
AF:
0.00154
AC:
133
AN:
86244
Gnomad4 FIN exome
AF:
0.00213
AC:
114
AN:
53402
Gnomad4 NFE exome
AF:
0.000865
AC:
962
AN:
1111700
Gnomad4 Remaining exome
AF:
0.000729
AC:
44
AN:
60368
Heterozygous variant carriers
0
69
138
208
277
346
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
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:
0.00116
AC:
177
AN:
152310
Hom.:
0
Cov.:
33
AF XY:
0.00118
AC XY:
88
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0000241
AC:
0.0000240558
AN:
0.0000240558
Gnomad4 AMR
AF:
0.00
AC:
0
AN:
0
Gnomad4 ASJ
AF:
0.00691
AC:
0.00691244
AN:
0.00691244
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00207
AC:
0.00207039
AN:
0.00207039
Gnomad4 FIN
AF:
0.00207
AC:
0.00207156
AN:
0.00207156
Gnomad4 NFE
AF:
0.00175
AC:
0.00174979
AN:
0.00174979
Gnomad4 OTH
AF:
0.000473
AC:
0.000473037
AN:
0.000473037
Heterozygous variant carriers
0
11
22
32
43
54
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
4
8
12
16
20
<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:
0.00178
Hom.:
1
Bravo
AF:
0.000854
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00244
AC:
21
ExAC
AF:
0.00128
AC:
155
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00109
EpiControl
AF:
0.00119

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Mar 25, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 16, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28550590) -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

FBN2: BS1 -

Congenital contractural arachnodactyly Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Aug 24, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

FBN2-related disorder Benign:1
Mar 12, 2020
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial thoracic aortic aneurysm and aortic dissection Benign:1
Jan 15, 2018
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome Benign:1
May 01, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Connective tissue disorder Benign:1
Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
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
0.26
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Uncertain
-0.040
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.73
D;.;D;D
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.93
D;.;.;D
M_CAP
Benign
0.071
D
MetaRNN
Benign
0.0095
T;T;T;T
MetaSVM
Uncertain
0.47
D
MutationAssessor
Uncertain
2.2
M;.;M;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-4.7
D;.;D;D
REVEL
Uncertain
0.62
Sift
Uncertain
0.011
D;.;D;D
Sift4G
Benign
0.11
.;.;.;T
Polyphen
0.96
P;.;P;D
Vest4
0.33
MVP
0.80
MPC
0.34
ClinPred
0.12
T
GERP RS
4.1
Varity_R
0.47
gMVP
0.72
Mutation Taster
=55/45
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34450503; hg19: chr5-127727722; COSMIC: COSV52531948; API