rs2291628

Positions:

chr5-128273941-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000262464.9(FBN2):c.7739C>T(p.Ser2580Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0746 in 1,613,668 control chromosomes in the GnomAD database, including 4,830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2580S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.071 ( 436 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4394 hom. )

Consequence

FBN2
ENST00000262464.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.193

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017172396).

BP6

Variant 5-128273941-G-A is Benign according to our data. Variant chr5-128273941-G-A is described in ClinVar as [Benign]. Clinvar id is 129051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128273941-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.7739C>T	p.Ser2580Leu	missense_variant	61/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 linkuse as main transcript	c.7586C>T	p.Ser2529Leu	missense_variant	60/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.7739C>T	p.Ser2580Leu	missense_variant	61/65	1	NM_001999.4	ENSP00000262464	P1	P35556-1
FBN2	ENST00000703783.1 linkuse as main transcript	n.4523C>T		non_coding_transcript_exon_variant	36/38

Frequencies

GnomAD3 genomes

AF:

0.0707

AC:

10753

AN:

152072

Hom.:

436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0754

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0693

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.0635

Gnomad SAS

AF:

0.0891

Gnomad FIN

AF:

0.0347

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0718

Gnomad OTH

AF:

0.0681

GnomAD3 exomes

AF:

0.0741

AC:

18579

AN:

250880

Hom.:

752

AF XY:

0.0736

AC XY:

9979

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0792

Gnomad AMR exome

AF:

0.0839

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.0603

Gnomad SAS exome

AF:

0.0809

Gnomad FIN exome

AF:

0.0440

Gnomad NFE exome

AF:

0.0735

Gnomad OTH exome

AF:

0.0735

GnomAD4 exome

AF:

0.0750

AC:

109644

AN:

1461478

Hom.:

4394

Cov.:

AF XY:

0.0753

AC XY:

54738

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.0753

Gnomad4 AMR exome

AF:

0.0808

Gnomad4 ASJ exome

AF:

0.106

Gnomad4 EAS exome

AF:

0.0616

Gnomad4 SAS exome

AF:

0.0811

Gnomad4 FIN exome

AF:

0.0435

Gnomad4 NFE exome

AF:

0.0751

Gnomad4 OTH exome

AF:

0.0813

GnomAD4 genome

AF:

0.0706

AC:

10751

AN:

152190

Hom.:

436

Cov.:

AF XY:

0.0683

AC XY:

5083

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0754

Gnomad4 AMR

AF:

0.0693

Gnomad4 ASJ

AF:

0.102

Gnomad4 EAS

AF:

0.0629

Gnomad4 SAS

AF:

0.0882

Gnomad4 FIN

AF:

0.0347

Gnomad4 NFE

AF:

0.0718

Gnomad4 OTH

AF:

0.0678

Alfa

AF:

0.0728

Hom.:

974

Bravo

AF:

0.0733

TwinsUK

AF:

0.0761

AC:

282

ALSPAC

AF:

0.0791

AC:

305

ESP6500AA

AF:

0.0813

AC:

358

ESP6500EA

AF:

0.0764

AC:

657

ExAC

AF:

0.0743

AC:

9017

Asia WGS

AF:

0.0660

AC:

230

AN:

3478

EpiCase

AF:

0.0733

EpiControl

AF:

0.0751

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ser2580Leu in exon 61 of FBN2: This variant is not expected to have clinical sig nificance because it has been identified in 8.1% (358/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2291628). -

Congenital contractural arachnodactyly

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2017	Variant summary: The FBN2 c.7739C>T (p.Ser2580Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. The variant of interest has been observed in a large, broad control population, ExAC, in 9006/121038 control chromosomes (359 homozygotes) at a frequency of 0.0744064, which is approximately 59525 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 classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2014

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

0.082

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;.;D

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.83

T;.;.

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.6

L;.;L

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.6

D;.;D

REVEL

Benign

0.23

Sift

Uncertain

0.029

D;.;D

Polyphen

0.0010

B;.;B

Vest4

0.19

MPC

0.22

ClinPred

0.021

GERP RS

3.9

Varity_R

0.14

gMVP

0.65

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over