5-128291568-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001999.4(FBN2):​c.6253C>G​(p.Pro2085Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00019 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

6
12

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.25
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.039460093).
BP6
Variant 5-128291568-G-C is Benign according to our data. Variant chr5-128291568-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 213344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000147 (215/1461726) while in subpopulation MID AF= 0.00173 (10/5768). AF 95% confidence interval is 0.00094. There are 1 homozygotes in gnomad4_exome. There are 121 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN2NM_001999.4 linkc.6253C>G p.Pro2085Ala missense_variant Exon 49 of 65 ENST00000262464.9 NP_001990.2 P35556-1
FBN2XM_017009228.3 linkc.6100C>G p.Pro2034Ala missense_variant Exon 48 of 64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkc.6253C>G p.Pro2085Ala missense_variant Exon 49 of 65 1 NM_001999.4 ENSP00000262464.4 P35556-1
FBN2ENST00000703783.1 linkn.3037C>G non_coding_transcript_exon_variant Exon 24 of 38
FBN2ENST00000703785.1 linkn.2956C>G non_coding_transcript_exon_variant Exon 23 of 27

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
152118
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00605
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000259
AC:
65
AN:
251186
Hom.:
0
AF XY:
0.000273
AC XY:
37
AN XY:
135750
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.00388
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000132
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000147
AC:
215
AN:
1461726
Hom.:
1
Cov.:
31
AF XY:
0.000166
AC XY:
121
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00375
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000666
Gnomad4 OTH exome
AF:
0.000381
GnomAD4 genome
AF:
0.000190
AC:
29
AN:
152236
Hom.:
1
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74420
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00605
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000360
Hom.:
0
Bravo
AF:
0.000181
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000173
AC:
21
EpiCase
AF:
0.000273
EpiControl
AF:
0.000415

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Jan 24, 2020
GeneDx
Significance: Likely benign
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, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2 related disorders (Collod-Beroud et al., 2003; Frederic et al., 2009); Reported in ClinVar (ClinVar Variant ID# 213344; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24833718) -

Sep 13, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Congenital contractural arachnodactyly Benign:2
Jan 13, 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. -

Dec 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
Jul 08, 2024
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
Aug 26, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely 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
Dec 31, 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Uncertain
0.67
D;.;D
Eigen
Benign
-0.054
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.73
T;.;.
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.039
T;T;T
MetaSVM
Uncertain
0.076
D
MutationAssessor
Benign
0.47
N;.;N
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-3.3
D;.;D
REVEL
Uncertain
0.47
Sift
Benign
0.28
T;.;T
Polyphen
0.090
B;.;B
Vest4
0.37
MVP
0.56
MPC
0.48
ClinPred
0.054
T
GERP RS
4.4
Varity_R
0.12
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs34845843; hg19: chr5-127627260; API