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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, 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=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 VariationId 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.

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.6931A>G	p.Met2311Val	missense	Exon 55 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.6931A>G	p.Met2311Val	missense	Exon 55 of 65	ENSP00000262464.4	P35556-1
FBN2	ENST00000939405.1		c.6832A>G	p.Met2278Val	missense	Exon 54 of 64	ENSP00000609464.1
FBN2	ENST00000939404.1		c.6778A>G	p.Met2260Val	missense	Exon 54 of 64	ENSP00000609463.1

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

Age Distribution

Exome Het

Exome Hom

Variant carriers

2272

4544

6816

9088

11360

<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:

0.117

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

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<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:

0.0719

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Congenital contractural arachnodactyly (2)

not provided (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.068

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.64

MetaRNN

Benign

0.00015

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.70

PhyloP100

1.8

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.45

REVEL

Benign

0.28

Sift

Benign

0.43

Polyphen

0.0

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

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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