NM_001999.4:c.8274C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001999.4(FBN2):c.8274C>T(p.Ser2758Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,570 control chromosomes in the GnomAD database, including 11,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1447 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9795 hom. )

Consequence

FBN2
NM_001999.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.364

Publications

14 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 5-128261826-G-A is Benign according to our data. Variant chr5-128261826-G-A is described in ClinVar as Benign. ClinVar VariationId is 129053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.364 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.8274C>T	p.Ser2758Ser	synonymous_variant	Exon 64 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 link	c.8121C>T	p.Ser2707Ser	synonymous_variant	Exon 63 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 link	c.8274C>T	p.Ser2758Ser	synonymous_variant	Exon 64 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19569

AN:

152020

Hom.:

1448

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.0905

Gnomad ASJ

AF:

0.0674

Gnomad EAS

AF:

0.0401

Gnomad SAS

AF:

0.0692

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.116

GnomAD2 exomes

AF:

0.102

AC:

25633

AN:

251166

AF XY:

0.100

show subpopulations

Gnomad AFR exome

AF:

0.173

Gnomad AMR exome

AF:

0.0703

Gnomad ASJ exome

AF:

0.0516

Gnomad EAS exome

AF:

0.0283

Gnomad FIN exome

AF:

0.145

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.112

AC:

163982

AN:

1461432

Hom.:

9795

Cov.:

AF XY:

0.111

AC XY:

80521

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.172

AC:

5754

AN:

33472

American (AMR)

AF:

0.0730

AC:

3263

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0552

AC:

1443

AN:

26134

East Asian (EAS)

AF:

0.0352

AC:

1399

AN:

39696

South Asian (SAS)

AF:

0.0644

AC:

5553

AN:

86252

European-Finnish (FIN)

AF:

0.137

AC:

7335

AN:

53414

Middle Eastern (MID)

AF:

0.0782

AC:

451

AN:

5768

European-Non Finnish (NFE)

AF:

0.119

AC:

132496

AN:

1111584

Other (OTH)

AF:

0.104

AC:

6288

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

8429

16858

25287

33716

42145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4746

9492

14238

18984

23730

<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:

0.129

AC:

19593

AN:

152138

Hom.:

1447

Cov.:

AF XY:

0.128

AC XY:

9533

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.175

AC:

7258

AN:

41492

American (AMR)

AF:

0.0904

AC:

1381

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0674

AC:

234

AN:

3472

East Asian (EAS)

AF:

0.0404

AC:

209

AN:

5178

South Asian (SAS)

AF:

0.0693

AC:

334

AN:

4820

European-Finnish (FIN)

AF:

0.146

AC:

1538

AN:

10570

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8263

AN:

68006

Other (OTH)

AF:

0.114

AC:

241

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

872

1744

2616

3488

4360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

206

412

618

824

1030

<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:

0.120

Hom.:

738

Bravo

AF:

0.125

Asia WGS

AF:

0.0490

AC:

171

AN:

3478

EpiCase

AF:

0.113

EpiControl

AF:

0.119

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ser2758Ser in exon 64 of FBN2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 17.3% (764/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10070365). -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital contractural arachnodactyly

Benign:4

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

- -

Nov 19, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

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.8274C>T (p.Ser2758Ser) variant involves the alteration of a non-conserved nucleotide causing a synonymous change that 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts no significant effect on ESE sites caused by the variant. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.1042542 (12655/121386 control chromosomes [778 homozygotes]), which is approximately 83403 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. -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Nov 25, 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

BayesDel_noAF

Benign

-0.48

CADD

Benign

4.6

(source)

DANN

Benign

0.53

PhyloP100

-0.36

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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