5-128286799-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001999.4(FBN2):c.6931A>G(p.Met2311Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,613,694 control chromosomes in the GnomAD database, including 12,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 2077 hom., cov: 33)

Exomes 𝑓: 0.071 ( 10631 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.82

Publications

26 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)

FBN2 links:

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=1.4686584E-4).

BP6

Variant 5-128286799-T-C is Benign according to our data. Variant chr5-128286799-T-C is described in ClinVar as [Benign]. Clinvar id is 129046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.6931A>G	p.Met2311Val	missense_variant	Exon 55 of 65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.6778A>G	p.Met2260Val	missense_variant	Exon 54 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 link	c.6931A>G	p.Met2311Val	missense_variant	Exon 55 of 65	1	NM_001999.4	ENSP00000262464.4		P35556-1
FBN2	ENST00000703783.1 link	n.3715A>G		non_coding_transcript_exon_variant	Exon 30 of 38

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17723

AN:

152100

Hom.:

2074

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0674

Gnomad ASJ

AF:

0.0516

Gnomad EAS

AF:

0.602

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.0499

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0456

Gnomad OTH

AF:

0.0875

GnomAD2 exomes

AF:

0.112

AC:

28018

AN:

251276

AF XY:

0.109

show subpopulations

Gnomad AFR exome

AF:

0.216

Gnomad AMR exome

AF:

0.0409

Gnomad ASJ exome

AF:

0.0564

Gnomad EAS exome

AF:

0.630

Gnomad FIN exome

AF:

0.0525

Gnomad NFE exome

AF:

0.0453

Gnomad OTH exome

AF:

0.0722

GnomAD4 exome

AF:

0.0707

AC:

103374

AN:

1461476

Hom.:

10631

Cov.:

AF XY:

0.0718

AC XY:

52216

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.214

AC:

7166

AN:

33462

American (AMR)

AF:

0.0418

AC:

1868

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0579

AC:

1514

AN:

26134

East Asian (EAS)

AF:

0.602

AC:

23886

AN:

39684

South Asian (SAS)

AF:

0.136

AC:

11738

AN:

86246

European-Finnish (FIN)

AF:

0.0514

AC:

2745

AN:

53418

Middle Eastern (MID)

AF:

0.0387

AC:

223

AN:

5766

European-Non Finnish (NFE)

AF:

0.0442

AC:

49166

AN:

1111658

Other (OTH)

AF:

0.0839

AC:

5068

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

4715

9430

14145

18860

23575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.117

AC:

17748

AN:

152218

Hom.:

2077

Cov.:

AF XY:

0.121

AC XY:

9022

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.214

AC:

8880

AN:

41526

American (AMR)

AF:

0.0671

AC:

1026

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0516

AC:

179

AN:

3470

East Asian (EAS)

AF:

0.602

AC:

3107

AN:

5164

South Asian (SAS)

AF:

0.150

AC:

724

AN:

4820

European-Finnish (FIN)

AF:

0.0499

AC:

529

AN:

10606

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0456

AC:

3104

AN:

68020

Other (OTH)

AF:

0.0899

AC:

190

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

715

1430

2144

2859

3574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0719

Hom.:

3212

Bravo

AF:

0.122

TwinsUK

AF:

0.0507

AC:

188

ALSPAC

AF:

0.0410

AC:

158

ESP6500AA

AF:

0.207

AC:

914

ESP6500EA

AF:

0.0416

AC:

358

ExAC

AF:

0.115

AC:

13976

Asia WGS

AF:

0.313

AC:

1088

AN:

3478

EpiCase

AF:

0.0411

EpiControl

AF:

0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Met2311Val in exon 55 of FBN2: This variant is not expected to have clinical sig nificance because it has been identified in 20.7% (914/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs32209). -

Nov 13, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The FBN2 c.6931A>G (p.Met2311Val) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in the large control database ExAC at a frequency of 0.1151322 (13966/121304 control chromosomes [2250 homozygotes]), which is approximately 92106 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Nov 24, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

0.064

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.21

T;.;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.068

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.64

T;.;.

MetaRNN

Benign

0.00015

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.70

N;.;N

PhyloP100

1.8

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.45

N;.;N

REVEL

Benign

0.28

Sift

Benign

0.43

T;.;T

Polyphen

0.0

B;.;B

Vest4

0.13

MPC

0.24

ClinPred

0.017

GERP RS

5.3

Varity_R

0.085

gMVP

0.68

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

5-128286799-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over