rs154001

Variant names:

Your query was ambiguous. Multiple possible variants found:

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:18

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
carpal tunnel syndrome
Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
macular degeneration, early-onset
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
familial thoracic aortic aneurysm and aortic dissection
Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.2893G>A	p.Val965Ile	missense	Exon 23 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBN2	ENST00000262464.9	TSL:1 MANE Select	c.2893G>A	p.Val965Ile	missense	Exon 23 of 65	ENSP00000262464.4	P35556-1
FBN2	ENST00000939405.1		c.2794G>A	p.Val932Ile	missense	Exon 22 of 64	ENSP00000609464.1
FBN2	ENST00000939404.1		c.2740G>A	p.Val914Ile	missense	Exon 22 of 64	ENSP00000609463.1

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital contractural arachnodactyly (6)

not specified (5)

not provided (2)

Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset (1)

Connective tissue disorder (1)

Ehlers-Danlos syndrome (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Macular degeneration, early-onset (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0000032

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.39

PhyloP100

4.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.30

REVEL

Benign

0.24

Sift

Benign

0.33

Sift4G

Benign

0.44

Polyphen

0.0010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over