5-128349443-C-T

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.2893G>A(p.Val965Ile) variant causes a missense change. The variant allele was found at a frequency of 0.694 in 1,613,198 control chromosomes in the GnomAD database, including 390,972 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.69 ( 35996 hom., cov: 32)

Exomes 𝑓: 0.69 ( 354976 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 4.11

Publications

57 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=3.1779655E-6).

BP6

Variant 5-128349443-C-T is Benign according to our data. Variant chr5-128349443-C-T is described in ClinVar as Benign. ClinVar VariationId is 129039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.2893G>A	p.Val965Ile	missense_variant	Exon 23 of 65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.2740G>A	p.Val914Ile	missense_variant	Exon 22 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 link	c.2893G>A	p.Val965Ile	missense_variant	Exon 23 of 65	1	NM_001999.4	ENSP00000262464.4		P35556-1
FBN2	ENST00000508989.5 link	c.2794G>A	p.Val932Ile	missense_variant	Exon 22 of 33	2		ENSP00000425596.1		D6RJI3

Frequencies

GnomAD3 genomes

AF:

0.686

AC:

104185

AN:

151884

Hom.:

35967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.620

Gnomad AMI

AF:

0.667

Gnomad AMR

AF:

0.748

Gnomad ASJ

AF:

0.758

Gnomad EAS

AF:

0.921

Gnomad SAS

AF:

0.739

Gnomad FIN

AF:

0.710

Gnomad MID

AF:

0.703

Gnomad NFE

AF:

0.683

Gnomad OTH

AF:

0.696

GnomAD2 exomes

AF:

0.728

AC:

182726

AN:

250892

AF XY:

0.725

show subpopulations

Gnomad AFR exome

AF:

0.621

Gnomad AMR exome

AF:

0.819

Gnomad ASJ exome

AF:

0.771

Gnomad EAS exome

AF:

0.939

Gnomad FIN exome

AF:

0.709

Gnomad NFE exome

AF:

0.682

Gnomad OTH exome

AF:

0.708

GnomAD4 exome

AF:

0.695

AC:

1015407

AN:

1461196

Hom.:

354976

Cov.:

AF XY:

0.696

AC XY:

505945

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.619

AC:

20699

AN:

33458

American (AMR)

AF:

0.810

AC:

36219

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.771

AC:

20136

AN:

26126

East Asian (EAS)

AF:

0.918

AC:

36433

AN:

39696

South Asian (SAS)

AF:

0.733

AC:

63233

AN:

86210

European-Finnish (FIN)

AF:

0.719

AC:

38389

AN:

53404

Middle Eastern (MID)

AF:

0.721

AC:

4155

AN:

5760

European-Non Finnish (NFE)

AF:

0.678

AC:

753964

AN:

1111478

Other (OTH)

AF:

0.699

AC:

42179

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

17047

34093

51140

68186

85233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19470

38940

58410

77880

97350

<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:

0.686

AC:

104264

AN:

152002

Hom.:

35996

Cov.:

AF XY:

0.690

AC XY:

51239

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.620

AC:

25680

AN:

41434

American (AMR)

AF:

0.748

AC:

11423

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.758

AC:

2633

AN:

3472

East Asian (EAS)

AF:

0.921

AC:

4757

AN:

5166

South Asian (SAS)

AF:

0.739

AC:

3566

AN:

4824

European-Finnish (FIN)

AF:

0.710

AC:

7492

AN:

10550

Middle Eastern (MID)

AF:

0.701

AC:

206

AN:

294

European-Non Finnish (NFE)

AF:

0.683

AC:

46424

AN:

67976

Other (OTH)

AF:

0.698

AC:

1476

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1698

3396

5094

6792

8490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.686

Hom.:

120509

Bravo

AF:

0.685

TwinsUK

AF:

0.683

AC:

2531

ALSPAC

AF:

0.688

AC:

2651

ESP6500AA

AF:

0.628

AC:

2766

ESP6500EA

AF:

0.680

AC:

5846

ExAC

AF:

0.723

AC:

87775

Asia WGS

AF:

0.813

AC:

2829

AN:

3478

EpiCase

AF:

0.680

EpiControl

AF:

0.679

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly

Benign:6

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 31, 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 specified

Benign:4

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. -

Dec 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a RefSeq error. The reference base (c.2893G) is the minor allele. This a llele (G) has been identified in 32% (2754/8600) of European American chromosome s and 37% (1640/4406) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs154001) and thus meets c riteria to be classified as benign. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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.2893G>A (p.Val965Ile) variant causes a missense change involving the alteration of a conserved nucleotide that 4/4 in silico tools (Mutation Taster not captured here due to low p-value) predict a benign outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 0.7233944 (87496/120952 (32094 homozygotes)), therefore, suggesting that the A allele is the major allele, the allele most commonly observed in the general population. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. 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 19, 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. -

Ehlers-Danlos syndrome

Benign:1

Jul 16, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macular degeneration, early-onset

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Jul 18, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset

Benign:1

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

T;.;.;T

MetaRNN

Benign

0.0000032

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.39

N;.;N;.

PhyloP100

4.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.30

N;.;N;N

REVEL

Benign

0.24

Sift

Benign

0.33

T;.;T;T

Sift4G

Benign

0.44

.;.;.;T

Polyphen

0.0010

B;.;B;B

Vest4

0.20

MPC

0.21

ClinPred

0.011

GERP RS

3.3

Varity_R

0.10

gMVP

0.13

Mutation Taster

=93/7

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