5-128366419-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001999.4(FBN2):c.2260G>A(p.Gly754Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00156 in 1,603,254 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G754R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:19

Conservation

PhyloP100: 4.59

Publications

10 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=0.011122942).

BP6

Variant 5-128366419-C-T is Benign according to our data. Variant chr5-128366419-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00141 (215/152086) while in subpopulation AMR AF = 0.00426 (65/15262). AF 95% confidence interval is 0.00343. There are 0 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 215 AD gene.

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.2260G>A	p.Gly754Ser	missense	Exon 17 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.2260G>A	p.Gly754Ser	missense	Exon 17 of 65	ENSP00000262464.4	P35556-1
FBN2	ENST00000939405.1		c.2161G>A	p.Gly721Ser	missense	Exon 16 of 64	ENSP00000609464.1
FBN2	ENST00000939404.1		c.2107G>A	p.Gly703Ser	missense	Exon 16 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

215

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00155

AC:

386

AN:

249594

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.000434

Gnomad AMR exome

AF:

0.00283

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000274

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00158

AC:

2293

AN:

1451168

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

1146

AN XY:

722404

show subpopulations

African (AFR)

AF:

0.000421

AC:

AN:

33276

American (AMR)

AF:

0.00295

AC:

131

AN:

44464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25968

East Asian (EAS)

AF:

0.000254

AC:

AN:

39366

South Asian (SAS)

AF:

0.00144

AC:

123

AN:

85616

European-Finnish (FIN)

AF:

0.000113

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.000873

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00174

AC:

1923

AN:

1103650

Other (OTH)

AF:

0.00135

AC:

AN:

59964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

190

284

379

474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.00141

AC:

215

AN:

152086

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

100

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

41528

American (AMR)

AF:

0.00426

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0000946

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00169

AC:

115

AN:

67960

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00159

Hom.:

Bravo

AF:

0.00148

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00175

AC:

ExAC

AF:

0.00148

AC:

180

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Congenital contractural arachnodactyly (3)

Connective tissue disorder (2)

not specified (2)

Brain aneurysm (1)

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

Ehlers-Danlos syndrome (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

FBN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.088

Eigen_PC

Benign

-0.045

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.66

M_CAP

Benign

0.076

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.096

MutationAssessor

Benign

1.0

PhyloP100

4.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.23

REVEL

Uncertain

0.61

Sift

Benign

0.084

Sift4G

Benign

0.40

Polyphen

0.98

Vest4

0.21

MVP

0.90

MPC

0.39

ClinPred

0.031

GERP RS

3.9

Varity_R

0.052

gMVP

0.65

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.10

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